programa de pós-graduação em medicina: endocrinologia
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UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS: ENDOCRINOLOGIA TÍTULO PAPEL DA IRISINA PLASMÁTICA E DA TAXA METABÓLICA DE REPOUSO NO CONTROLE DO PESO CORPORAL E PERFIL METABÓLICO DE PACIENTES COM DIFERENTES GRAUS DE OBESIDADE TESE DE DOUTORADO MILENE MOEHLECKE Porto Alegre, 2016
Transcript of programa de pós-graduação em medicina: endocrinologia
UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS:
ENDOCRINOLOGIA
TÍTULO
PAPEL DA IRISINA PLASMÁTICA E DA TAXA METABÓLICA
DE REPOUSO NO CONTROLE DO PESO CORPORAL E PERFIL
METABÓLICO DE PACIENTES COM DIFERENTES GRAUS DE
OBESIDADE
TESE DE DOUTORADO
MILENE MOEHLECKE
Porto Alegre, 2016
UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS MÉDICAS:
ENDOCRINOLOGIA
MILENE MOEHLECKE
Tese de Doutorado apresentada ao
Programa de Pós-Graduação em
Ciências Médicas: Endocrinologia da
Universidade Federal do Rio Grande
do Sul (UFRGS) como requisito para
obtenção do título de Doutora em
Endocrinologia.
Orientadora: Profa Dra. Cristiane Bauermann Leitão
Porto Alegre, 2016
Catalogação Biblioteca FAMED/HCPA
Esta tese de Doutorado será apresentada no formato exigido pelo Programa de
Pós-Graduação em Ciências Médicas: Endocrinologia. Ela será constituída de: 1)
Resumo da Tese; 2) Introdução; 3) Artigo de revisão publicado nos Archives of
Endocrinology and Metabolism em 2016; 4) Artigo original ainda não submetido; 4)
Artigo original (em processo de resposta aos revisores no periódico Surgery for Obesity
and Related Diseases); 5) Artigo de revisão realizado durante o doutorado e sem relação
direta com a tese, publicado no periódico American Journal of Perinatology Reports em
2016.
Moehlecke, Milene Papel da irisina plasmática e da taxa metabólica de repouso no controle do peso corporal e perfil metabólico de pacientes com diferentes graus de obesidade / Milene Moehlecke. – 2016.
Orientadora. Cristiane Bauermann Leitão. – 2016. 111 f. Tese (Doutorado) – Universidade Federal do Rio Grande do Sul. Faculdade de Medicina. Programa de Pós-Graduação em Ciências Médicas: Endocrinologia. Porto Alegre, BR-RS, 2016.
1. Obesidade 2. Irisina 3. Taxa metabólica de repouso 4. Cirurgia bariátrica 5. Composição corporal. I. Leitão, Cristiane Bauermann, oriente. II. Título.
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DEDICATÓRIA
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
Goethe
A todos aqueles que participaram dessa trajetória.
AGRADECIMENTOS
A minha orientadora Profa. Dra. Cristiane Bauermann Leitão que, desde a época em
que iniciei como aluna de iniciação científica, foi a minha maior inspiração, pois não há modo
de ensinar mais forte e suave do que o próprio exemplo e tu és um exemplo de competência,
humanismo, humildade e bom humor acima de tudo. Obrigada por fazer parte da minha
formação, como médica e como ser humano.
A Profa. Dra Daisy Crispim pela parceria e pelas contribuições fundamentais para a
realização do projeto como um todo.
À colega de pós-graduação, doutoranda Jakeline Rheinheimer, pela dedicação e
cuidado excepcional com o processamento das amostras do estudo.
Ao Prof. Dr. Manoel Roberto Maciel Trindade, pela cooperação ao compartilhar
comigo seus pacientes do ambulatório da equipe da Cirurgia do Aparelho Digestivo.
À colega Ana Carolina Martins Mazzuca e aos alunos de iniciação científica, Ivan
Zepeda e Lucas Oliveira Junqueira e Silva, pela importante colaboração na execução do
estudo.
À amiga Carina Andriatta Blume, pela amizade nascida junto com a pós-graduação.
Obrigada pelo incentivo e pela participação especial nas várias etapas do estudo.
Aos meus pais, um agradecimento especial por me proporcionarem os meios
necessários para a materialização dos meus sonhos, sempre com muito amor e apoio.
Obrigada por me mostrarem que para ser feliz é preciso muito pouco, basta apenas
valorizarmos o essencial.
A minha irmã, minha outra fonte de inspiração, uma mulher de personalidade,
generosa e linda.
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A minha amada afilhada Rafaela, por me proporcionar imensa alegria diariamente com
seu jeitinho meigo e carinhoso, e também por recarregar minha energia em períodos mais
difíceis nesses últimos anos.
Ao meu namorado, Géris Mazzuti, pelo apoio fundamental e pelo incentivo constante
por entender o quão importante é para mim a pesquisa e o trabalho como pesquisadora.
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SUMÁRIO
Agradecimentos .............................................................................................................. v
Lista de Tabelas e Figuras .............................................................................................. ix
Lista de Abreviaturas ...................................................................................................... xi
Capítulo 1 – Resumo ...................................................................................................... 12
Capítulo 2 – Introdução .............................. .................................................................... 14
Referências .............................................................................................................. 17
Capítulo 3 – Artigo de revisão: Determinants of body weight regulation in humans: a
review…………………………………………………………...................................... 19
References ................................................................................................................. 40
Capítulo 4 - Considerações finais e perspectivas futuras............................................ .... 47
Anexo – Artigo de revisão realizado e publicado durante o doutorado e sem relação direta
com a tese: Low gestational weight gain in obese women and pregnancy outcomes: a
review............................................................................................................................. 49
References ................................................................................................................ 63
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LISTA DE TABELAS E FIGURAS
Capítulo 3: Determinants of body weight regulation in humans: a review
Table 1. Summary of key peptides and neurotransmitters involved in the regulation of body
weight ..................................................................................................... 39
Figure 1. Regulation of energy homeostasis between central nervous system and peripheral
signals ..................................................................................................... 41
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LISTA DE ABREVIATURAS
ACOG American College of Obstetricians and Gynecologists
AGA Adequate for gestational age
AgRP Agouti-related peptide
ARC Neurons of the arcuate nucleus
ATP Adenosina trifosfato
BAT Brown adipose tissue
BMI Body mass index
CART Cocaine and amphetamine regulated transcript
CCK Cholecystokinin
CI Confidence interval
CNS Central nervous system
CRH Corticotropin releasing hormone
CV Coefficients of variability
DXA Dual-energy absorptiometry X-ray
EWL Excess weight loss
FFM Fat-free mass
FM Fat mass
FNDC5 Fibronecting type III domain containing 5
GDM Gestational diabetes
GEE Generalized estimating equation
GLP-1 Glucagon like-peptide 1
GLP-1R GLP-1 receptor
GWG Gestational weight gain
HOMA-IR Homeostasis model of assessment – insulin resistance
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IMC Índice de massa corporal
IOM Institute of Medicine
IPAQ-LF Long-form International Physical Activity Questionnaire
LGA Large for gestation age
MCH Melanin-concentrating hormone
MCR Melanocortin receptors
MC4R Melanocortin 4 receptor
ɑ-MSH Alpha-melanocyte-stimulating hormone
NAFLD Non-alcoholic liver disease
NPY Neuropeptide Y
NST Nucleus of the solitary tract
NTD Neural tube defects
PGC-1α Peroxisome proliferator activated receptor γ coactivator1α
POMC Pro-opiomelanocortin
PPAR-gama Peroxisome proliferator-activated receptor gamma
PYY Peptide YY
REE Resting energy expenditure
RYGB Roux-en-Y gastric bypass
SD Standard deviation
SGA Small for gestational age
SNS Sympathetic nervous system
TMR Taxa metabólica de repouso
TNF- alpha Tumor necrosis factor – alpha
UCP1 Uncoupling protein 1
WAT White adipose tissue
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WC Waist circumference
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Resumo
Introdução: A obesidade, doença crônica e multifatorial, decorre de uma predisposição
genética associada a fatores ambientais e ao desequilíbrio energético. A taxa metabólica de
repouso (TMR) representa o principal componente do gasto energético e está diretamente
relacionada à massa livre de gordura. A participação do tecido adiposo marrom na regulação
do gasto energético em adultos tem sido avaliada nos últimos anos. Em 2012, um hormônio
denominado irisina foi descrito participar deste processo através da indução de uma
subpopulação de adipócitos brancos em um subtipo nomeado bege, com características
funcionais semelhantes ao marrom. Em roedores, este hormônio foi associado ao aumento da
termogênese, redução do peso corporal e melhora do perfil glicêmico. Em humanos,
entretanto, sua contribuição para a regulação energética bem como seu envolvimento em
distúrbios metabólicos permanece incerto. Objetivos: Esta tese é composta de dois estudos
originais. O primeiro avaliou os níveis de irisina em pacientes com diferentes categorias de
índice de massa corporal (IMC), bem como sua associação com parâmetros antropométricos,
metabólicos e de composição corporal. Além disso, foram comparados os níveis de irisina nos
pacientes após perda de peso induzida cirurgicamente a controles obesos. Já o segundo
artigo, teve como objetivo avaliar as mudanças na TMR conforme as modificações da
composição corporal após cirurgia bariátrica e a influência da TMR sobre o excesso de peso
perdido em 12 e 18 meses. Métodos: O primeiro artigo foi uma coorte prospectiva e o
segundo, um estudo observacional prospectivo. Pacientes com idade superior a 18 anos foram
avaliados entre 2013 a 2015. Para avaliação da irisina plasmática, 77 pacientes foram
classificados conforme o seu IMC nos seguintes grupos: Grupo 1: IMC entre 18,5 a 27 kg/m²,
n = 11; Grupo 2: IMC entre 30 kg/m² a 39,9 kg/m², n = 36 e Grupo 3: IMC maior ou igual a
40 kg/m², n = 30. Os pacientes dos Grupos 1 e 2 foram submetidos a qualquer cirurgia
abdominal eletiva, exceto cirurgia bariátrica e os pacientes do Grupo 3 ao bypass gástrico em
Y de Roux. Os 3 grupos foram avaliados no basal e os Grupos 2 e 3 foram reavaliados em 6
meses. Já para avaliação da TMR após a perda de peso induzida pela cirurgia bariátrica, 30
pacientes foram avaliados imediatamente antes e após 6 meses da cirurgia. A TMR foi
avaliada por calorimetria indireta, a composição corporal pela absorciometria por raio X
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com dupla energia e os níveis plasmáticos de irisina por kit Elisa (Phoenix Pharmaceuticals).
Resultados: A maioria dos pacientes avaliados em ambos os estudos foi composta de
mulheres (80%), brancos (82%), e com média de idade de 46±14 anos. Em relação ao estudo
sobre irisina, no basal, os pacientes do Grupo 3 apresentaram mediana de irisina menor em
relação ao Grupo 2: 8,4 (7,8 – 10,5) vs 9,9 (8,9 – 12,0) ng/ml, respectivamente; P = 0,014.
Uma correlação inversa foi observada entre os níveis de irisina e o peso corporal (r = -0,246;
P = 0,042), circunferência da cintura (r = -0,272; P = 0,024), glicemia de jejum (r = -0,259; P
= 0,039), hemoglobina glicada (r = -0,283 P = 0,024), e triglicerídeos (r = -0,414 P <0,001).
Os níveis de irisina foram positivamente correlacionados ao HDL (r = 0,280; P = 0,029). Em
6 meses, todas as medidas antropométricas e de composição corporal foram similares, exceto
pela menor TMR corrigida para o peso (P = 0,038) e para massa livre de gordura (P = 0,044),
e os níveis de irisina, que permaneceram menores nos pacientes do Grupo 3 (P = 0,006). Dos
30 pacientes avaliados no segundo estudo, a média de IMC foi de 49 ± 9 kg/m², peso corporal
de 128 ± 19 kg, metade do qual constituído por massa gorda (50 ± 5%). A TMR no basal foi
2297 ± 182 kcal/dia. O excesso de peso perdido foi de 54 ± 16%, sendo 45% como massa
gorda e 24% como massa livre de gordura. A TMR reduziu 19% durante o seguimento (-405
± 108 kcal/dia; P <0,001). Pacientes com uma redução superior a 405 kcal/dia em 6 meses
apresentaram menor excesso de peso perdido em 18 meses (r = -0,612; P = 0,035).
Conclusão: Os níveis de irisina estão reduzidos nos pacientes com obesidade grau 3 (IMC
≥40 kg/m²), bem como os níveis de irisina mostraram uma correlação inversa com parâmetros
metabólicos relacionados à ação da insulina, sugerindo um provável envolvimento deste
hormônio em estados de resistência insulínica, como a obesidade e o diabetes tipo 2. Além
disso, pacientes submetidos à cirurgia bariátrica que apresentaram uma maior redução na
TMR em 6 meses exibiram um menor excesso de peso perdido em longo prazo.
Palavras-chave: Irisina; Obesidade; Cirurgia bariátrica; Bypass gástrico em
Y Roux; Diabetes tipo 2; Taxa metabólica de repouso.
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Capítulo 2 - Introdução
O avanço científico sobre o reconhecimento das propriedades endócrinas e
metabólicas do tecido adiposo bem como a constatação sobre sua capacidade em produzir
hormônios, as chamadas adipocinas, atuantes na patogênese de distúrbios metabólicos como a
obesidade, diabetes tipo 2 e doença hepática gordurosa não alcoólica, está revolucionando
conceitos sobre a sua biologia (1). Ademais, a compreensão detalhada das suas propriedades
funcionais relacionadas a distúrbios metabólicos contribuirá para melhorar o prognóstico de
tais doenças, cuja prevalência vem crescendo de forma preocupante, sobretudo em países em
desenvolvimento (1).
O tecido adiposo é o principal reservatório energético do organismo. Nos mamíferos,
dois tipos de tecido adiposo são descritos: o branco e o marrom, com propriedades
metabólicas distintas (2). O adipócito branco armazena os triacilglicerois em uma única e
grande gota lipídica, ocupando aproximadamente 85 a 90% do citoplasma (3). Já os
adipócitos marrons podem ser identificados em aglomerados, mesmo dentro do tecido adiposo
branco, sendo caracterizados por conter grande quantidade de proteína desacopladora 1
(UCP1 ou termogenina) e de mitocôndrias, ambas relacionadas à termogênese e à regulação
da temperatura corporal (3).
Embora descrito em certos mamíferos desde 1551, a compreensão de que o tecido
adiposo marrom é encontrado em todos os mamíferos ocorreu apenas no último século (2). A
termogênese é uma das suas funções que tem sido reconhecida nos últimos 40 anos (2).
Finalmente, seu envolvimento nos diversos tipos de insuficiência metabólica, como um
possível órgão antiobesidade, tem sido discutido há apenas três décadas (4).
Como referido acima, o adipócito marrom é densamente enriquecido de mitocôndrias
que, por não possuírem o complexo enzimático necessário para a síntese de adenosina
trifosfato (ATP), utilizam a energia liberada pela oxidação de metabólitos, principalmente
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ácidos graxos, para geração de calor (5). Esse processo ocorre porque a UCP1, uma proteína
da membrana mitocondrial interna do adipócito marrom, atua como um canal de próton que
descarrega a energia gerada pelo acúmulo de prótons no espaço intermembranoso das
mitocôndrias durante as reações oxidativas do ciclo de Krebs, desviando esses prótons do
complexo F1F0 (ATP sintase) e impedindo a síntese de ATP, permitindo que se dissipe em
calor a energia armazenada na mitocôndria (2).
PGC1-α (do inglês, peroxisome proliferator-activated receptor γ coactivator1-alfa) é
um coativador transcricional que participa de muitos programas biológicos relacionados ao
metabolismo energético. Originalmente descrito como um coativador do PPAR-δ, modulando
a expressão da UCP1 e da termogênese no tecido adiposo marrom (6), tem recentemente sido
descrito seu papel como ativador da biogênese mitocondrial e do metabolismo oxidativo em
muitos tipos celulares (7). PGC1-α é induzido no músculo pelo exercício, estimulando muitos
dos efeitos benéficos conhecidos do exercício no músculo: biogênese mitocondrial,
angiogênese e mudança do tipo de fibra muscular (8). O beneficio da expressão aumentada do
PGC1-α pode ir além do tecido muscular em si. A hiperexpressão de PGC1-α em roedores
geneticamente modificados foi associada à melhora do perfil glicêmico e a um menor ganho
de peso (9). Tal achado sugere que o PGC1-α estimula a expressão de uma série de produtos
genéticos musculares, denominadas miocinas, que são potencialmente secretadas durante o
exercício, incluindo o FNDC5 (do inglês, fibronectin type III domain containing 5), com ação
em outros tecidos.
O FNDC5, ao ser proteoliticamente clivado, libera na circulação uma miocina
denominada irisina. Este hormônio, por sua vez, é induzido pelo exercício e atua estimulando
a diferenciação de precursores de adipócitos brancos em um terceiro tipo de célula adiposa -
bege, efeito conhecido como browning, sendo identificada pela maior expressão de UCP1
nessas células (10). Dessa forma, a conversão de parte das células adiposas brancas em bege
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pode contribuir para o aumento da termogênese e consequentemente do gasto energético,
potencialmente refletindo-se sobre um menor ganho de peso e proteção contra o surgimento
de doenças metabólicas como o diabetes tipo 2. Experimento em camundongos submetidos a
exercício resistido durante três semanas mostrou aumento na expressão tanto de PGC-1α
quanto do FNDC5, além de uma elevação em 65% na concentração sérica de irisina após o
período de estímulo com exercício (9).
Resultados similares foram encontrados em um experimento realizado em humanos
adultos e saudáveis submetidos a 10 semanas de exercício regular. Um aumento de 2 vezes
nos níveis plasmáticos de irisina foi documentado em relação ao grupo controle (11). Então, a
irisina parece estar presente tanto em roedores como em humanos, com homologia idêntica,
aumentando após o exercício e com efeitos comprovados sobre a termogênese e regulação do
peso corporal em modelos animais.
Em humanos, sua participação na diferenciação de células adiposas, bem como sua
contribuição para a termogênese e envolvimento em vias metabólicas necessita ser melhor
avaliada.
Dessa forma, esta tese tem os seguintes objetivos:
1. Revisar os mecanismos biológicos responsáveis pela regulação do peso corporal,
detalhando as vias aferentes, eferentes bem como a integração destas informações no sistema
nervoso central;
2. Avaliar se existe associação entre os níveis plasmáticos de irisina e medidas
antropométricas, de composição corporal e parâmetros metabólicos em pacientes com
diferentes graus de obesidade comparando-os a indivíduos eutróficos;
3. Avaliar as mudanças na taxa metabólica de repouso 6 meses após a cirurgia
bariátrica conforme as mudanças na composição corporal e a repercussão das modificações da
taxa metabólica de repouso sobre o excesso de peso perdido em 12 e 18 meses.
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Referências
1. Fonseca-Alaniz MH, Takada J, Alonso-Vale MI, Lima FB. The adipose tissue as a
regulatory center of the metabolism. Arch Endocrinol Metab 2006;50(2):216-29.
2. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological
significance. Physiol Rev 2004;84(1):277-359.
3. Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy
adults. NEJM 2009;360(15):1518-25.
4. Rothwell NJ, Stock MJ. A role for brown adipose tissue in diet-induced
thermogenesis. Nature 1979;281(5726):31-5.
5. Brondani LA, Assmann TS, Duarte GC, Gross JL, Canani LH, Crispim D. The role of
the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus.
Arch Endocrinol Metab 2012;56(4):215-25.
6. Cereijo R, Giralt M, Villarroya F. Thermogenic brown and beige/brite adipogenesis in
humans. Ann Med 2015;47(2):169-77.
7. Gali Ramamoorthy T, Laverny G, Schlagowski AI, et al. The transcriptional
coregulator PGC-1beta controls mitochondrial function and anti-oxidant defence in skeletal
muscles. Nat Comm 2015;6:10210.
8. Bostrom P, Wu J, Jedrychowski MP, et al. A PGC1-alpha-dependent myokine that
drives brown-fat-like development of white fat and thermogenesis. Nature
2012;481(7382):463-8.
9. Xu X, Ying Z, Cai M, et al. Exercise ameliorates high-fat diet-induced metabolic and
vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose
tissue. Am J Physiol Regul Integr Comp Physiol. 2011;300(5):1115-25.
10. Pedersen BK. A muscular twist on the fate of fat. NEJM 2012;366(16):1544-5.
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11. Vind BF, Pehmoller C, Treebak JT, et al. Impaired insulin-induced site-specific
phosphorylation of TBC1 domain family, member 4 (TBC1D4) in skeletal muscle of type 2
diabetes patients is restored by endurance exercise-training. Diabetologia 2011;54(1):157-67.
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Determinants of body weight regulation in humans: a review
Abbreviated title: Review of body weight regulation
Milene Moehlecke1, Luis Henrique Canani
1, Lucas Oliveira Junqueira e Silva
2, Manoel
Roberto Maciel Trindade3, Rogerio Friedman
1, Cristiane Bauermann Leitão
1
1Endocrine Division, Serviço de Endocrinologia do Hospital de Clínicas de
Porto Alegre, Rua Ramiro Barcelos 2350, Prédio 12, 4º andar, 90035-003 Porto
Alegre, Rio Grande do Sul, Brazil
2Graduate student, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre,
Rio Grande do Sul, Brazil.
3Digestive Surgery Division, Serviço de Cirurgia do Aparelho Digestivo do Hospital de Clínicas de
Porto Alegre, Rio Grande do Sul, Brazil
Milene Moehlecke*
Corresponding author*: Serviço de Endocrinologia do Hospital de Clínicas de Porto Alegre
Rua Ramiro Barcelos, 2350
Prédio 12 - 4º andar
Porto Alegre – RS, Brasil
CEP: 90035-003
55 51 33598246
Artigo publicado na revista Archives of Endocrinology and Metabolism 2016 Feb 23. pii:
S2359-39972016005002104
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Abstract
Body weight is regulated by the ability of hypothalamic neurons to orchestrate
behavioral, endocrine and autonomic responses via afferent and efferent pathways to the
brainstem and the periphery. Weight maintenance requires a balance between energy intake
and energy expenditure. Although several components that participate in energy homeostasis
have been identified, there is a need to know in more detail their actions as well as their
interactions with environmental and psychosocial factors in the development of human
obesity.
In this review, we examine the role of systemic mediators such as leptin, ghrelin and
insulin, which act in the central nervous system by activating or inhibiting neuropeptide Y,
Agouti-related peptide protein, melanocortin, transcript related to cocaine and amphetamine,
and others. As a result, modifications in energy homeostasis occur through regulation of
appetite and energy expenditure. We also examine compensatory changes in the circulating
levels of several peripheral hormones after diet-induced weight loss.
Keywords: Appetite Regulation, Energy Metabolism, Energy Expenditure, Body
Weight
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Introduction
Obesity is a chronic multifactorial disease of complex etiology, resulting from the
chronic disruption between energy intake and energy expenditure, involving genetic,
environmental, lifestyle and emotional factors. The body mass index (BMI) calculated by
dividing weight (in kilograms) by height (in meters) squared, is one of the available tools for
assessment of overall adiposity. The prevalence of overweight, defined as BMI between 25
and 29.9 kg/m2 and obesity, as BMI greater than or equal to 30 kg/m
2 has increased
progressively in recent decades. Data from the National Health and Nutrition Examination
Survey show that approximately 70% of North American adults are overweight and 35% are
obese. Obese individuals have an increased risk of obesity-related chronic complications and
mortality from all causes proportional to the increasing of BMI (1). The addition of waist
circumference (WC) to BMI seems to predict a greater variance in health risk than does BMI
alone (2). Increased central adiposity is associated with an increased risk of morbidity and
mortality [11]. In adults with a BMI of 25 to 34.9 kg/m2, a WC greater than 102 cm (40 in)
for men and 88 cm (35 in) for women is associated with a greater risk of chronic
complications (2).
In this review, we synthesize the main neurohumoral mechanisms involved in the
regulation of energy metabolism and the evidence for their possible association with the
development of obesity. In addition, we discuss briefly about compensatory changes in the
circulating levels of several peripheral hormones after weight loss for understanding the
physiological basis of weight regain after diet-induced weight loss.
Integration of afferent and efferent system and complex regulator
The appetite control derives from a variety of afferent stimuli (afferent pathways) to be
processed in the central nervous system (CNS) (processing unit) and finally signals the intake
and regulates energy store (4). Sense organs, humoral signals, nutrients and vagals afferents
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are involved in feeding in the short term (5). Processing unit of the CNS includes
hypothalamus and brain stem. Efferent system, a complex regulator of appetite and satiety,
includes limbic cortex, thalamus, brain stem, insula, hippocampus and base nuclei that taken
together with autonomic thermogenic effectors will regulate the energy expenditure (Figure
1). The interaction between these components finally will result in increased or decreased in
energy stores.
Afferent system: hormones signaling energy reserves
Role of the adipose tissue
Adipose tissue is the major reservoir of energy in the body. In mammals, two types of
adipose tissue occur: white and brown both directly regulated by the autonomic nervous
system (6). Sympathetic innervation is mainly related to the catabolic actions, such as
lipolysis, mediated by β-adrenergic receptor-dependent activity of the enzyme hormone-
sensitive lipase (6). On the other hand, the parasympathetic activation is involved in anabolic
effects, such as uptake of glucose and fatty acids stimulated by insulin (6).
Recent evidence has shown that the adipose tissue also plays an important role in the
integration of endocrine, metabolic and inflammatory signals to control energy homeostasis,
through the production of a variety of bioactive proteins, together referred to as "adipokines",
which include: leptin, adiponectin, resistin, visfatin, tumor necrosis factor – alpha (TNF-
alpha), plasminogen inhibitor type 1, among others. Some of these are associated with
disruption in metabolism and obesity and will be described below.
Leptin
Leptin is produced mainly in white adipose tissue and its concentration, in normal
individuals, is proportional to the amount of adipose tissue, being higher in subcutaneous
adipose tissue compared to visceral tissue (7). Leptin, which is stimulated by insulin, acts by
inhibiting the release of neuropeptide Y (NPY)/Agouti-related peptide (AgRP), and through
23
23
increased activation of neurons of the arcuate nucleus (ARC) of the hypothalamus that
express the pro-opiomelanocortin (POMC) (8). Thus, the NPY/AgRP neurons are thought to
constitute a potent feeding system that is actively opposed by the POMC/cocaine and
amphetamine regulated transcript (CART) satiety system (9). Leptin also stimulates other
anorexigenic peptides such as corticotropin releasing hormone (CRH) and CART, resulting in
catabolic effects of prolonged action and decreased food intake with increased energy
expenditure (9). In polygenic obesity, increased leptin levels suggest resistance to its
anorexigenic effects. It is likely that a failure in its production and / or action on its
hypothalamic receptor could lead to a positive energy balance, generating hyperphagia and
severe obesity (10). In human or animal obesity models with lack the leptin receptor or ligand,
high leptin levels do not inhibit the feeding; its absence is a strong stimulus to induce feeding
though (9). This can be considered an evolutionarily advantageous system as it allows for
excess energy storage when resources are transiently available but drives feeding behavior
under more limiting conditions (11). However, leptin signaling becomes maladaptive under
obesogenic environment with easy access to highly palatable and energy dense foods.
Visfatin
Visfatin is an adipokine highly expressed in visceral fat that has been associated to
numerous proinflammatory effects and glucose homeostasis (12). Obesity and type 2 diabetes
were associated with elevated circulating plasma visfatin in meta-analysis of observational
studies (13). It has been suggested that visfatin is significantly increased during the process of
adipogenesis, being involved in adipocyte differentiation and proliferation (14). Its elevated
plasma levels in association with insulin resistance and type 2 diabetes are probably a
consequence of the hyperglycaemia milieu (13). Its exact biological action remains uncertain
being necessary further investigation to clarify the connection between visfatin, and
pathologic conditions as obesity and type 2 diabetes (13).
24
24
Adiponectin
Adiponectin appears to play an important role in the modulation of glucose and lipid
metabolism in insulin sensitive tissues, both in animals and humans models (15). Its
production is stimulated by PPAR-gama and inhibited by catecholamines, and TNF- alpha
(16). It acts systemically through two receptors, adipo-R1 and adipo-R2 (expressed in muscle
tissue and in hepatocytes, respectively), increasing sensitivity to insulin, reducing hepatic
glucose production and stimulating fatty acid oxidation (16). In humans, plasma adiponectin
levels are significantly lower in states of insulin resistance, including type 2 diabetes (17).
Two loci related to metabolic syndrome components were identified in the same chromosome
(3q27) where the adiponectin gene is located, reinforcing the role of this hormone in obesity
(18). The fact that obesity is characterized by a state of adiponectin deficiency makes this an
interesting target for possible therapeutic interventions.
Resistin
The main biological effects of resistin are associated with increases in blood glucose
levels and obesity in some animal models, partially explained as a consequence of increased
hepatic glucose production (19). In humans, resistin reduces insulin-stimulated glucose uptake
in isolated adipocytes. The mechanisms underlying these effects remain unclear, although
data aim to the suppression of AMP-activated protein kinase activity by resistin, primarily in
the liver, due to activation of cytokine stimulation-3 suppressor. The phenotypes of
humanized resistin transgenic mice suggest similar roles of murine and human resistin in
insulin resistance (20). Elevated resistin levels are associated with greater risk for type 2
diabetes, increased inflammatory markers and atherosclerosis (21).
Role of the intestine
In the gut, chemo and mechano-receptors give information about the amount of
nutrients that is temporarily stored in the gastrointestinal tract (8). In the stomach, nutrients
25
25
are perceived by vagal stretch and sensors present in the gastric mucosa (8). Moreover,
intestinal peptides, stimulated by food intake, mediate satiety centers in the brain stem.
Signals received by the brain stem centers to regulate long term weight use neural connections
with the hypothalamus to regulate total daily intake, by adjusting the size of the meals, their
number or both (22).
Ghrelin
Ghrelin is a potent orexigenic hormone that stimulates food intake (10). The stomach
is the primary site of ghrelin, although lower concentrations may be found in other organs as
small intestine and hypothalamus (10). It is likely that this peptide is responsible for the start
of a meal. Its levels are elevated one to two hours before the meal, and are decreased soon
after (23). Its orexigenic action results from activation of NPY/AgRP neurons in the ARC
(10). The pharmacological blockade of ghrelin receptors in these neurons attenuates food
intake in rodents (24). The exogenous administration of ghrelin is associated with increased
food intake, reduced resting energy expenditure and catabolism in the adipose tissue (25).
Glucagon like-peptide 1 (GLP-1)
GLP-1, derived from the proglucagon gene, is the prototypical incretin hormone. GLP-
1 release is triggered by ingestion of carbohydrates, fats, and protein and seems to reflect, at
least in part, the direct sensing of luminal nutrients by the apical processes of the intestinal L-
cells and the hindbrain, primarily in the nucleus of the solitary tract (26). GLP-1 acts as
satiety signals through the GLP-1 receptor (GLP-1R). GLP-1R can also be stimulated
exogenously via long lasting GLP-1 analogs (27). In humans, peripheral GLP-1
administration to normal and diabetic subjects induces satiety and reduces food intake in short
term studies (28). Chronic continuous GLP-1 administration to human diabetic subjects was
associated with modest weight loss (28). The effects of GLP-1 on appetite may be mediated in
part via inhibition of gastric emptying and also reflect direct effects of GLP-1 on satiety and
26
26
induction of taste aversion (29). GLP-1R stimulation reduces food reward behavior (28).
Peripherally, GLP-1 stimulates lipolysis, adiponectin expression and increases thermogenesis
with increased energy expenditure (30).
Peptide YY (PYY)
PYY is released in the gastrointestinal tract in the postprandial period. It is important
in prompting the end of the meal (8). It acts by inhibiting the activity of neurons NPY/AgRP
and stimulating POMC/CART in the ARC of the hypothalamus. Infusion of PYY at
physiological doses results in inhibition of gastric emptying and gastric acid and pancreatic
exocrine secretion (31). These effects are mediated by direct action of PYY on the dorsal
vagal complex (31). The peripheral administration of pharmacological doses of this peptide
seems to have a short anorectic effect in humans, suggesting that PYY functions as a satiety
factor (32). The mechanisms underlying the action of PYY in reducing food intake have not
been fully elucidated. Its contribution in long term regulation of energy deposits, however,
needs to be better evaluated.
Cholecystokinin (CCK)
CCK is released approximately 15 min after meal initiation by the presence of lipids
and proteins, inducing anorectic effect by vagal afferent pathways (33). There are several
known bioactive forms of CCK, such as CCK-8 and CCK-58 and two types of CCK
receptors, CCKA and CCKB (33). CCKA (also known as CCK1) seems to play a more
important role in food intake regulation. CCK regulates short term feeding behavior in mice
through selectively satiation, namely, the termination of eating at meal end (34). Deficits
in satiation signaling during obesogenic feeding have been proposed to play a role in
hyperphagia and weight gain in animals prone to become obese. The effects of CCK on
suppression of food intake of high fat fed obese prone and resistant rats and its role on lipid-
induced satiation was recently examined (35). Obese prone rats have reduced feeding
27
27
responses to exogenous CCK and have deficits in endogenous CCK signaling compared to
resistant rats (35). These results suggest that high fat feeding leads to impairments in lipid-
induced CCK satiation signaling in obese-prone rats, potentially contributing to hyperphagia
and weight gain. Moreover, to evaluate CCK function on meal size and intermeal interval,
CCK was injected in experimental rodents during every spontaneous meal by intraperitoneal
catheters with extended of both (36). However, the absence of CCK signaling seems has no
effect on long term energy homeostasis. The influence of exogenous CCK-8 on satiety effect
was first reported in obese humans in 1982 and revealed that subjects stopped eating sooner
during CCK-8 administration, even though maintaining the same eat rate (37). Studies have
been shown that in lean individuals, the increase in postprandial CCK levels is high and fast,
which may result in earlier occurrence of satiation, while in obese individuals, postprandial
CCK levels remain increased for longer (38).
Insulin
Insulin is a circulating afferent signal, whose concentrations increasing with BMI,
with many central effects similar to leptin (10). Mice without insulin receptors in the CNS
develop hyperphagia and fat deposition, while insulin agonists exert the opposite effect (39).
In view of insulin and leptin regulate body weight via negative feedback, the exogenous
administration of these hormones would presumably promote weight loss (10). However,
obese individuals become resistant to insulin and leptin, and remain hyperphagic despite high
circulating levels of both hormones (40). Researchers have attempted to elucidate the
mechanisms associated with resistance to the action of these hormones, as well as to develop
more effective agonists of leptin and insulin analogues with selective action in the CNS,
without peripheral anabolic effects (10).
Central circuits: regulation of energy homeostasis
28
28
The regulation of energy homeostasis occurs through interconnection between a wide
variety of signals from the gastrointestinal tract, via either sensory afferents or via circulation,
at the dorsal vagal complex to multiple brain circuits to affect autonomic neuronal pathways
and endocrine organs (41). This interaction will result in appetite control, in satiety, defined as
sensation of satisfaction or fullness, and in the pleasure associated with food, related to
palatability and reward derived from food (9).
The hypothalamus and the brain stem act as the two main centers, which receive and
integrate peripheral signals that then cross-regulate each other and communicate with higher
brain regions such as the anterior forebrain mesolimbic reward system (22). Peptides can
regulate both appetite and energy expenditure as neurotransmitters can act in an even more
complex way, through multiple receptors. Its effects may vary according to the anatomical
region involved (42). A summary of the principal peptides and neurotransmitters involved in
the regulation of body weight are presented in Table 1.
Hypothalamus
Within the hypothalamus, several hypothalamic sites are thought to be key in
regulating energy homeostasis. The ARC of the hypothalamus contains two populations of
neurons that continuously monitor signals reflecting energy status and promote the
appropriate behavioral and metabolic responses to changes in energy demand. Neurons
making POMC decrease food intake and increase energy expenditure through activation of G
protein-coupled melanocortin receptors (MCR) via release of alpha-melanocyte-stimulating
hormone (ɑ-MSH) (Figure 1) (43). AgRP acts antagonizing the action of α-MSH at the
melanocortin 4 receptor (MC4R). Overexpression of AgRP can lead to obesity (44). MC4R is
widely found in the hypothalamus and activation of this receptor by α-MSH reduces food
intake (45). Deletions or mutations in the MC4R are associated with obesity. It is estimated
29
29
that 5% of cases of early-onset and severe obesity are the result of heterozygous mutations of
MC4R (46).
Neurons expressing orexigenic neuropeptides as NPY, AgRP, MCH neurons act
increasing feeding and decreasing energy expenditure primarily by opposing the
anorexigenic/catabolic actions of the POMC through both via competitive inhibition of
melanocortin tone at the postsynaptic level and via direct inhibition of POMC (43). The
opposite does not occur, favoring dietary intake and decreased energy expenditure in the
absence of reciprocal inhibition of the POMC system on the NPY / AgRP.
Two neuropeptides are expressed by neurons in the lateral hypothalamus: melanin-
concentrating hormone (MCH) and orexins (42). MCH stimulates appetite, possibly induced
by the flavor of foods (47). The MCH producers neurons in the lateral hypothalamus are
projected to the centers of smell and other areas of cerebral cortex, being inhibited by MSH
producers neurons and neurons stimulated by NPY/AgRP (47). Orexins have secondary
effects on food intake (42). The exact sites targeted by MCH neurons and orexins for
induction of feeding behavior remains being determined.
Brain stem
The brain stem is classically understood as the center for detection and response to
hunger/satiety signals (47). The dorsal vagal complex is comprised of the nucleus of the
solitary tract (NST), the dorsal motor nucleus of the vagus (vagal motor neurons) and the area
postrema. Sensory afferent signals carried by glossopharyngeal and vagus nerves include
indications of taste, gastric stretch, and levels of glucose and lipids in the liver and portal vein.
This information is relayed to the dorsal motor nucleus of the vagus, located ventrally to the
NTS, which is the primary site of motor effectors into the intestine (47).
Efferent system: regulation of energy expenditure, efferent autonomic and endocrine
systems
30
30
Energy expenditure
Ultimately, obesity results from an imbalance between energy input and energy
output. Energy expenditure comprises combustion of substrates by oxygen and body’s work
and is divided into four types: (1) obligatory thermogenesis, related to cellular metabolism,
functioning of organs, maintenance of the body’s vital functions; (2) postprandial
thermogenesis, or the thermal effect of food; (3) thermogenesis resulting from physical
activity; and (4) adaptive thermogenesis (48). It has been postulated that a deficit in energy
expenditure could contribute to the storage of triglycerides leading to obesity.
The obligatory thermogenesis is also referred to as resting energy expenditure (REE),
representing approximately 70% of energy expenditure (42). Most studies do not support the
involvement of a defect in REE in the development of obesity. Obese individuals usually have
greater REE than lean persons because greater lean and adipose tissue cell mass excess (49).
Ravussin et al concluded that the most important factor determining both the increased REE
and energy expenditure during 24 h in obese when compared to control subjects is the
increased free fat mass (49). Some studies, however, have shown that a low energy
expenditure could play a role in energy imbalance and obesity. A longitudinal study showed
that a low rate of energy expenditure adjusted for body composition could be a predictor of
weight gain in population prone to obesity (50). Another prospective study evaluated the
energy metabolism and weight changes in Pima Indians, one of the most obese populations in
the world (51). In this study, both total caloric intake and REE were significantly associated
with changes in weight in an average period of four years. Weight loss is associated with a
reduction in energy expenditure that is out of proportion to changes in lean body mass, and it
appears to persist indefinitely as long as the reduced weight is maintained (52).
The oxygen consumption increased (approximately 50 kcal to 100 kcal over a period
of 4 hours to 8 hours) after the ingestion of food is named thermic effect of food (53). There
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31
are many factors that can influence it, as meal size, composition meal, physical activity and
stands out the insulin resistance. In animal models, the association between obesity and
decreased sympathetic nervous system (SNS) activity has consistently been found (53). The
normal response (increased oxygen consumption) to a high fat diet is absent in mice without
β-adrenergic receptor (53). In humans, it is likely that obese subjects have smaller but
potentially important reduction in thermic effect of food from the insulin resistance and
attenuated SNS activity (53).
The most variable part of energy expenditure is that corresponding to physical activity:
exercise and non-exercise activity thermogenesis, which includes involuntary activities such
as spontaneous muscle contractions, maintaining posture and involuntary movements, both
representing 20% of energy expenditure (47). Physical activity has short and long-term effects
on energy expenditure. Acutely, it induces an increase in oxygen consumption (47). Irisin
levels are increased in response to acute exercise as described in the section “Role of muscle
tissue”. In addition, it may have long-term effects on REE, which may be promoted by
stimulants of adaptive thermogenesis, as excess calories (42). It is unknown whether obese
persons expend less total energy on daily physical activity than lean individuals do or if they
are less active (54). Obese persons expend the same amount of energy as lean persons to
perform the same amount of work during non–weight bearing activity (42). However, during
weight-bearing activities, obese persons expend more energy than lean ones because more
work is required to carry their greater body weight (55). It is estimated that in obese persons,
the energy deficit created by exercise is usually much less and requires more effort than the
energy deficit created by a reduced-calorie diet (47).
Adaptive thermogenesis corresponds to changes in energy expenditure as a function of
thyroid hormones administration, exposure to cold and food intake, and accounts for 10% of
energy expenditure (48). Thyroid hormones play a critical role in both obligatory and adaptive
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32
thermogenesis. In complete absence of thyroid hormone, REE could be reduced by at least
30% (56). In response to an environment with low temperature, the SNS encourages a
thermogenic response of brown adipose tissue with rapid increase in T3 levels. Although
thyroid hormones are critical for the regulation of REE and adaptive thermogenesis, their
effects on weight in the absence of diseases such as hyper or hypothyroidism are difficult to
determine. The effects of administration of daily injections of T3 or GC-1 (a synthetic
analogue, selective for the β type thyroid receptor) at equimolar doses, for 6 weeks, on
different metabolic parameters were assessed in rodents (57). In this study, animals treated
with T3 or GC-1 lost 70% and 20% of the fat mass, respectively, compared to controls, which
gained 80% of fat mass, with no difference in the gain of fat-free mass. The development of
synthetic analogues of thyroid hormones with selective effect on the REE, adaptive
thermogenesis and metabolic profile, without side effects on other organs, is a promising area
in the treatment of obesity (57).
The brown adipose tissue regulates energy expenditure through adaptive
thermogenesis, a process that results in heat production by mitochondria to maintain normal
body temperature. The activity of brown adipose tissue increases during childhood and
adolescence, reaching a peak at 13 years of age, with a tendency to decrease progressively
with increased age (58). The brown adipose tissue was not previously associated with
thermogenesis in adults. However, observational studies using positron emission tomography
and computerized tomography with 18F-fluorodeoxyglucose have shown the presence of
metabolically active brown adipose tissue in healthy adults when exposed to cold (59). Thus,
the activation of brown adipose tissue may be an important component of energy expenditure
stimulated by cold in adults. Moreover, the activity of brown adipose tissue is inversely
related to BMI, age and percentage of body fat (58).
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33
Irisin
Irisin is secreted by myocytes and appears to mediate the beneficial effects of exercise
on metabolism. Irisin, secreted into the blood as a product of fibronecting type III domain
containing 5 (FNDC5), is induced by exercise and stimulates the transformation of white
adipose tissue into brown adipose tissue, an effect known as "browning" of subcutaneous
adipose tissue, by increasing the expression of uncoupling protein 1 (UCP1, thermogenin)
(60). This effect leads to increased energy expenditure, potentially reflected in the reduction
of body weight and the incidence of type 2 diabetes. Böstrom and colleagues examined the
effect of exercise on FNDC5 expression in the skeletal muscle of mice after 3 weeks of
resistance exercise (60). There was a significant increase in both FNDC5 and plasma levels of
irisin, resulting in improved glucose tolerance and reduced weight of mice submitted to
exercise (60). Similar to what occurs in mice, the gene is expressed in the muscle of humans
(61). Although irisin is identical in humans and rodents, the reproducibility of the effects of
different stimuli in rodents is still doubtful in humans. Since that formation of brown adipose
tissue has shown antidiabetes and antiobesity effects in both murine and human models,
administration of analogues of irisin is a potentially attractive therapeutic target for metabolic
disorders, especially in patients unable to perform physical activity (62).
Efferent autonomic
Regarding the contribution of the SNS, several neuropeptides, monoamines and drugs
involved in the modulation of food intake and energy storage have reciprocal effects on
sympathetic activity and adaptive thermogenesis (63). Both serotonin and norepinephrine
reduce food intake and increase sympathetic activity (63). Mice expressing no adrenergic
receptors develop severe obesity due to impaired diet-induced thermogenesis (63). Decreased
SNS activity has been described in humans with obesity (63). Reduced sympathetic activity
plays an opposite role in the adipose tissue: in white adipose tissue, there is a recruitment of
34
34
new adipocytes that will result in hypertrophy and overdevelopment this cell; in the brown
adipose tissue, an decrease in SNS activity will result in an overall decreased thermogenesis
by two ways: decreasing the amount and activity of UCP1 and, decreasing the number of
brown adipocytes (6).
Gut microbiota
Dietary habits are considered one of the main factors that contribute to the diversity of
human gut microbiota (64). Microbial changes in the human gut have been proposed as
another possible cause of obesity (65). Many studies have reported shifts in the relative
abundance of bacterial communities in the gut microbiota of obese relative to normal-weight
individuals, and each study has attempted to link obesity with a species- or genus-specific
composition profile of the gut microbiota (64). Meta-analyses revealed no difference in the
Bacteroidetes concentrations between obese and normal weight humans (66). Other meta-
analyses revealed that obese subjects present less Firmicutes, Bifidobacteria and
Methanobrevibacter spp. than nonobese subjects do in their gut flora (8). However, it is still
poorly understood how the dynamics and composition of intestinal microbiota are affected by
diet or other lifestyle factors. It is believed that gut microbiota could affect body weight in
experimental animals (and probably in humans) by several mechanisms, including effects on
energy metabolism, low-grade inflammation, and altered gut permeability (67). Further
studies should be conducted to clarify how gut microbial communities normally operate, and
how they may be altered by probiotic, prebiotic, and antibiotic interventions to promote
weight loss (64).
Short and long-term persistence of hormonal adaptations to weight loss
After a period of weight loss induced by dieting, the body lay hold on to a series of
adjustments in order to restrict the weight loss and prevent starvation. Calorie restriction
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35
induces compensatory short and long term mechanisms that will promote regain weight in
most patients in treatment. The extremely high failure rate (>80%) to keep the reduced weight
after successful weight loss is due to adaptation processes of the body to maintain body
energy stores (68). Increased hunger and decreased satiety are secondary to increased ghrelin
following weight loss (69). Moreover, significant and persistent reductions in energy
expenditure as well as reductions in anorexigenic hormones as leptin appear to persist for at
least one year following weight reduction and may remain altered indefinitely in a manner
that promotes increased energy intake and ultimately weight regain (69). As previously
documented, obese individuals undergoing weight loss through diet exhibit an approximate
28% decrease in energy expenditure (70).
Conclusion
The determination of body weight results, ultimately, from a complex interaction of
peripheral signals involving the gastrointestinal tract, adipose tissue and muscle with the
CNS. The increasingly detailed mapping of effector pathways that regulate body weight in
response to afferent information from peripheral adiposity signals has produced a series of
targets for new anti-obesity drugs. Although several components that participate in energy
homeostasis have been identified, there is a need to know further details about their actions as
well as their interactions with environmental and psychosocial factors in the development of
human obesity. For most obese persons, negative energy balance is more readily achieved by
decreasing food intake than by increasing physical activity. Therefore, dietary intervention is
considered the cornerstone of weight-loss therapy. Weight-loss diets generally involve
modifications of energy content and macronutrient composition. However, the degree of
weight loss achieved primarily depends on the energy content, rather than the relative
macronutrient composition of the diet. Since the adaptive biologic responses to weight loss
36
36
are prone to promote energy accumulation, individuals must restrict energy intake and
increase energy expenditure indefinitely to avoid weight regain.
Abbreviations
AgRP: Agouti-related peptide protein; BMI: body mass index; CART: cocaine and amphetamine
regulated transcript; CCK: cholecystokinin; CNS: central nervous system; CRH: corticotropin
releasing hormone; FNDC5: fibronectin type III domain containing 5; GC-1: synthetic analogue
selective thyroid receptor β type; GLP-1: Glucagon like-peptide 1; GLP-1R: GLP-1 receptor; MCH:
melanin-concentrating hormone; MC4R: melanocortin 4 receptor; MSH: melanocyte stimulating
hormone; NPY: neuropeptide Y; NST: Nucleus of the solitary tract; POMC: pro-opiomelanocortin;
PYY: peptide YY; REE: resting energy expenditure; SNS: sympathetic nervous system; UCP1:
uncoupling protein 1; WC: waist circumference.
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37
Table 1. Summary of key peptides and neurotransmitters involved in the regulation of body weight
Production site Stimulation of
production
Production
inhibitors Action
Effects on
the
regulation
of hunger
Effects on
energy
expenditure
AFFERENT SYSTEM
Leptin Adipose tissue
Postprandial
period Insulin
Fast Inhibition of NPY / AgRP
Increased release of α-
MSH, CRH and CART
Anorexigeni
c action Increases
Ghrelin Stomach,
primarily Fast
Preprandial period Postprandial
period Activation of NPY / AgRP
Orexigenic
action Decreases
GLP-1
Small intestine Postprandial
period Fast
Increases secretion of
insulin-dependent glucose Increases fatty acid
synthesis
Anorexigeni
c action No effect
Insulin Pancreas
Postprandial
period Overnight fast
Preprandial period Production of catabolic
neuropeptides
Anorexigeni
c action in
the CNS No effect
CENTRAL NERVOUS SYSTEM
NPY Medial
hypothalamus,
Arcuate nucleus
Fast Ghrelin
Leptin Glucose
Increases food intake Increases lipogenesis in
animals
Orexigenic
action Decreases
AgRP Medial
hypothalamus,
Arcuate nucleus
Fast Ghrelin
Leptin Antagonizes the effects of
MC4R Orexigenic
action Decreases
MCH Lateral
hypothalamus Flavor of foods
MSH-producing
neurons Uncertain
Probable link with the NAc Orexigenic
action No effect
α-MSH Medial
hypothalamus,
Arcuate nucleus Leptin AgRP Agonist for the MC4R
Anorexigeni
c action Increases
EFFERENT SYSTEM
Irisin Myocytes Exercise Unknown Induces "browning" of the
SAT by increasing the
No direct
effect on Increases
38
38
AgRP, Agouti-related peptide protein; α-MSH, alpha-melanocyte-stimulating hormone; CART, cocaine and amphetamine
regulated transcript; CNS, Central Nervous System; CRH, corticotropin releasing hormone; GLP1, glucagon like- peptide 1;
MC4R, melanocortin 4 receptor; MCH, melanin-concentrating hormone;; NAc, nucleus accumbens; NPY, neuropeptide Y;
SAT, subcutaneous adipose tissue; UCP1; uncoupling protein 1.
expression of UCP1 hunger
Serotoni
n/
Norepin
ephrine
Autonomous
nervous system Environmental
factors: low
temperatures, diet
Weight loss Increases sympathetic
activity Thermogenesis
Lipolysis in adipose tissue
Anorexigeni
c action Increases
Thyroid
hormon
es
Thyroid Exposure to cold Fever
High calorie diet
Critical illness
Caloric restriction Drugs
Regulates obligatory and
adaptive thermogenesis Modulates
appetite
according to
the state of
hyper or
hypothyroid
ism
Increases
39
39
Figure 1. Regulation of energy homeostasis between central nervous system and
peripheral signals (adapted 5, 47). The determination of body weight results from a complex
interaction of peripheral signals from the gastrointestinal tract, adipose tissue with the CNS. The
hypothalamic control of energy homeostasis comes from the ability of hypothalamic neurons to
orchestrate behavioral, endocrine and autonomic responses, via afferent and efferent pathways to the
brain stem and the periphery. In the muscle, peroxisome proliferator activated receptor γ coactivator
1α (PGC-1α) stimulates the expression of the membrane protein fibronectin type III domain
containing 5 (FNDC5), which is proteolytically cleaved to form irisin, a myokine that drives the
transformation of white fat cells into brite cells, an effect known as "browning" of subcutaneous
adipose tissue. PYY = peptide YY; CCK = cholecystokinin; GLP-1 = Glucagon like-peptide 1.
Competing interests
The authors declare that they have no competing interests.
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Considerações finais e perspectivas futuras
A prevalência de sobrepeso e obesidade tem ganhado proporções epidêmicas nas
últimas décadas, com crescimento alarmante, sobretudo, em países em desenvolvimento como
o Brasil. Ademais, comorbidades reconhecidamente associadas ao excesso de peso, tais como
diabetes tipo 2, hipertensão arterial sistêmica, doença cardiovascular, câncer, dentre outras,
têm igualmente tornado-se mais frequentes, aumentando a morbimortalidade e onerando o
sistema de saúde público.
O mapeamento detalhado das vias eferentes bem como do processamento das
informações no sistema nervoso central em resposta aos estímulos aferentes permitirá o
desenvolvimento de novas drogas para o tratamento da obesidade.
Nesse sentido, a descoberta da irisina, uma miocina liberada na circulação mediante
estímulo como a atividade física, tem ganhado notória repercussão por estar envolvida em
processos relacionados à termogênese e regulação de vias metabólicas relacionadas à
resistência à ação da insulina, obesidade, doença hepática gordurosa não alcoólica, dentre
outras, em modelos animais.
Em roedores, o aumento da liberação de irisina na circulação, seja mediante exercício
seja pela criação de camundongos geneticamente modificados para expressar PGC1-α, tem
levado à diferenciação de precursores de adipócitos brancos em beges, com aumento da
UCP1, uma proteína envolvida na dissipação de calor proveniente da energia química em
nível mitocondrial e consequentemente aumento da termogênese, redução do peso corporal,
além da melhora na sinalização de vias metabólicas envolvidas na homeostase glicêmica e
lipídica.
Em humanos, a função exata da irisina precisa ser melhor elucidada. Até o momento,
permanecem lacunas a serem preenchidas sobre o mecanismo de ação molecular da irisina,
assim como as vias de transdução de sinal desta miocina.
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O entendimento do sistema como um todo envolvido até a sua liberação na circulação,
ou seja, o sistema PGC1-α – FNDC5 – irisina – órgãos-alvo, em indivíduos hígidos bem
como em situações de doença, possibilitará o desenvolvimento de novas terapias
antiobesidade e antidiabetes, sobretudo em pacientes com alguma restrição à atividade física.
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Low gestational weight gain in obese women and pregnancy outcomes: a review.
Running head: Low gestational weight gain in obese pregnant
Keywords: Gestational weight gain, pre-pregnancy body mass index, pregnancy outcomes
Milene Moehlecke1, Fabíola Costenaro
1, Angela AJ Reichelt
2, Maria Lúcia R Oppermann
3,
Cristiane B Leitão1,2
1Post-Graduate Program in Medical Sciences: Endocrinology– Universidade Federal do Rio Grande do
Sul, Brazil
²Endocrine Division, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil
3Gynecology and Obstetrics Department, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul,
Brazil
Corresponding author*: Endocrine Division - Hospital de Clínicas de Porto Alegre
Rua Ramiro Barcelos, 2350
Prédio 12 - 4º andar
Porto Alegre – RS, Brasil
CEP: 90035-003
Artigo publicado no American Journal of Perinatology (AJP Rep. 2016 Mar;6(1):e77-82)
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ABSTRACT
Obesity during pregnancy and excessive weight gain during this period is associated
with a number of maternal-fetal and neonatal complications. Moreover, a significant
percentage of women experience weight retention in the postpartum period, especially those
with excessive weight gain during pregnancy. The recommendations from the 2009 Institute
of Medicine were based on observational studies which have consistently shown that women
with weight gain within the recommended limits experienced better outcomes during
pregnancy. In patients with obesity, however, there is not a recommendation for weight gain
according to class of obesity. This review, therefore, aims to evaluate the evidence on key
maternal and fetal complications related to low weight gain during pregnancy in obese and
overweight patients.
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INTRODUCTION
Obesity prevalence has risen worldwide significantly in recent decades. Estimates
from the National Health and Nutrition Examination Survey (NHANES) show that
approximately 70% of adult Americans are overweight (defined as body mass index [BMI]
greater than or equal to 25 kg/m²) or obese (BMI greater than or equal to 30 kg/m²) (1).
Notably, about a quarter of women retain more than 4 kg after pregnancy (2). Pre-pregnancy
weight and gestational weight gain (GWG) are important determinants of weight retention
maintenance over female lifespan (3).
In 2009, the Institute of Medicine (IOM) launched new GWG recommendations,
which were based on pre-pregnancy BMI (4). Lower weight gains were recognized as safe for
obese women, but the guideline did not address specific obesity classes (5). This paper
emphasizes the importance of being assessed fetal growth especially in the management of
GWG in obese patients. In this review, we intend to focus mainly on aspects related to weight
gain in class I–III obese pregnant women, as well as discuss the effects of lower than
recommended GWG on maternal and neonatal outcomes.
Methods
The search strategy included electronic bibliographic databases: MEDLINE and The
Cochrane Library. The terms were related to “pregnancy and weight” describing population
and/or outcomes. There was no date limit for publication. The maternal and fetal outcomes
evaluated were: preeclampsia, cesarean or instrumental delivery, postpartum hemorrhage,
weight retention, fetal growth, fetal distress, and Apgar scores for the baby at 1 and 5 minutes
after birth, respectively.
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RECOMMENDATIONS ON WEIGHT GAIN DURING PREGANCY
HISTORICAL OVERVIEW
The first recommendations on GWG were published in the 1970s and were developed
to account for high rates of infant and childhood mortality (6). At that time, it has been
recognized the positive association between lower GWG and low or very low weight birth.
For this reason, the American College of Obstetricians and Gynecologists (ACOG)
recommended a total GWG of 10 kg, opposite to the usual practice, that consisted of
recommending an approximate 6,8 kg of GWG (5).
Since then, GWG recommendations have been gradually increasing. In 1990, by the
first time, the Nutrition During Pregnancy Committee advised that GWG should be set
accordingly to pre-pregnancy BMI, in order to optimize fetal growth and pregnancy
outcomes (7). Recommendations were based on weight-height tables of the Metropolitan Life
Insurance (7).
Despite the 1990 IOM recommendations on GWG, important changes in the
demographic and epidemiological profiles of obesity in pregnancy occurred worldwide. The
increasing obesity epidemics also affects reproductive age women (5). Several studies
described remarkable GWG, far above recommendations, especially among overweight or
obese women (8). It was estimated that 37% of normal pre-pregnancy BMI weight women,
and 64% of overweight women, gained weight above the 1990 IOM recommendations (5).
So, due to the association of both excessive GWG and higher pre-pregnancy BMI with poor
maternal and fetal outcomes, a reassessment of criteria was launched in 2009 (5). Recent
meta-analysis of observational studies showed that the impact on maternal and fetal outcomes
is related to class of obesity in pregnancy (9).
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CURRENT RECOMMENDATIONS
The 2009 IOM guidelines (Table 1) development were based on BMI categories of
the World Health Organization (10). Recommendations included lower GWG in obese
women (5 to 9 kg or 11 to 20 lbs) (5). These recommendations were endorsed by ACOG (11),
and by the National Institute for Health and Care Excellence (12).
Current recommendations are based on observational studies that had consistently
shown improved pregnancy outcomes when GWG attended the recommendations of the
2009 IOM position statement (5).
The appropriate GWG for obese women, however, remains unclear. So far, there is no
official recommendation stratified by obesity classes. Few studies examined the effects of
diverse GWG on obstetric outcomes in obese women and there are some evidences that low
GWG and even weight loss could improve both maternal and fetal outcomes (13-15). Dietetic
interventions associated with a GWG as low as 3.84 kg were associated with decreased risk
of preeclampsia and shoulder dystocia, and no effect on newborn weight (16).
ASSOCIATED FACTORS
Many hormonal and genetic factors are responsible for the variability in maternal
metabolism during and after pregnancy. Leptin is correlated with the amount of adipose
tissue, and its secretion is stimulated by insulin. Higher concentrations of leptin occur in the
third trimester, concurrently to the physiologic hyperinsulinemia characteristic of that period.
Higher leptin levels were associated with greater GWG and postpartum weight retention in
observational studies (17). Elevated levels of sex steroids, such as high progesterone, can
affect insulin resistance which, in turn, could result in higher fat accumulation during
pregnancy and postpartum weight retention (17).
Several other factors such as ethnicity, age, marital status, socioeconomic status,
cultural beliefs, smoking and physical activity can contribute to the variability of GWG (18),
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as described below. Longitudinal studies recorded an average of GWG in African-descent
women 3 to 4 times higher than that of the Caucasian women after adjustment for pre-
pregnancy weight (19, 20).
Pregnancy in adolescence has been associated with increased risk of preterm delivery,
low birth weight and neonatal mortality (21). Current recommendations suggest that pregnant
adolescents should gain weight according to pre-pregnancy BMI, except for those aged 16
years or less whose menarche occurred within the last 2 years, due to the risk of
compromising final height (5). Conversely, in women over 35 years, a significantly higher
risk of adverse outcomes during pregnancy, such as stillbirth, low birth weight, preterm
delivery and small for gestational age (SGA) baby, has been recorded (22, 23). Moreover,
older women also have higher risk of hypertension, gestational diabetes (GDM), placenta
previa and placental abruption (24).
Regular physical activity can modulate GWG. The results of a recent meta-analysis
showed that women who engage in a program of aerobic or resistance training in the first or
second trimesters (20 to 60 minutes three times a week) had a lower (610 g) weight gain
compared to the control group, with no significant impact on fetal growth (25).
EFFECTS OF LOW WEIGHT GAIN GESTATIONAL
MATERNAL OUTCOMES
GDM, preeclampsia, cesarean or instrumental delivery, postpartum hemorrhage and
weight retention, are maternal adverse outcomes associated with excessive GWG and higher
pre-pregnancy BMI (8, 26). Studies evaluating GWG across different classes of obesity,
found insufficient weight gain or even weight loss during pregnancy associated with a
decreased risk of preeclampsia, postpartum hemorrhage, instrumental and cesarean delivery
and postpartum weight retention (13, 27).
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Preeclampsia
The risk of preeclampsia raises two fold in overweight and three fold in obese pregnant
women (28), showing a gradient proportional to the increase in BMI (29). Blomberg et al.
evaluated the effect of weight loss or insufficient GWG in more than 46,000 Swedish
pregnancies complicated by obesity (30). In this population-based cohort study, class III
obese women who gained up to 4.9 kg during pregnancy had a lower risk of preeclampsia
with unaffected risk of low Apgar score, SGA, and large for gestational age (31), or fetal
distress compared with same class obese women gaining weight within the 2009 IOM
recommendations. However, there was a twofold increased risk in SGA among class III obese
women who lost weight. Recent meta-analysis showed reduced risk of 10% for preeclampsia
in pregnant with GWG below the IOM guidelines (9).
Postpartum hemorrhage
A recent retrospective cohort study from the Consortium on Safe Labor, including
20,950 American obese women with a singleton term live birth, , described maternal and
neonatal outcomes according to weight change and BMI class (32). Low GWG (0 to 4.9 kg)
or weight loss were associated with a non-significant decrease in postpartum hemorrhage
rates for women with obesity class I-III. Blomberg et al. reported a significant increase in
postpartum hemorrhage attributable to uterine atony at rates proportional to obesity class (13,
32).
Cesarean and instrumental delivery
Potential confounding factors to be considered when evaluating rates of cesarean
delivery associated with excess GWG are the route of previous delivery in multiparous
women and the presence of comorbidities such as preeclampsia and GDM which most of the
studies do not adjust as covariates (5).
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A prospective population-based Norwegian study showed a linear increased risk of
cesarean delivery according to pre-pregnancy BMI after adjustments for parity (33). Recently,
based on a retrospective, observational database from the ACOG, the authors evaluated the
probability of cesarean and operative vaginal delivery for each weight change categories
using the IOM 2009 recommendations (32). Predicted probability of cesarean delivery
increased linearly as weight increases for all obesity classes, whereas operative vaginal
delivery did not vary significantly with weight change. When stratified by parity, multiparous
class III obese women with low GWG (0 to 4.9 kg) had a 33% reduced risk of cesarean
delivery, whereas no effect for multiparous class I-II obese women was observed. Blomberg
et al. showed that class I-III obese women who lost weight during pregnancy had a lower risk
(24 to 34%) of cesarean delivery (13).
Postpartum weight retention
Most studies described weight retention between 0.4 to 3.8 kg after pregnancy, with
different lenghts of follow-up, extended up to 156 months after delivery (34, 35). GWG
seems to be the most important predictor for postpartum weight retention (34). A recent meta-
analysis of nine observational studies classified women by the 2009 IOM criteria and found
that, compared with women with adequate GWG, those with lower GWG had significant less
postpartum weight retention, an average of -2.99 kg at short and medium interval follow-up
(36). Another meta-analysis suggested that women who exceeded GWG have a long term
trend of greater postpartum weight retention with increased risk of overweight or obesity at
21 years of follow-up (37). Nevertheless, the contribution of socioeconomic factors, cultural
practices, lifestyle changes, breastfeeding and other related behaviors for postpartum weight
retention must be elucidate.
FETAL, NEONATAL AND CHILDHOOD OUTCOMES
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Maternal weight gain above the 2009 IOM recommendations have been strongly
associated to an increased birth weight, later obesity and its metabolic consequences
throughout life (5). However, a lower GWG among obese women seems to reduce outcomes
such as fetal distress, low Apgar score, LGA, although with controversial effect on SGA risk.
Fetal growth
Birth weight related to gestational age is an important determinant of sibling
outcomes. Newborns are classified as adequate for gestational age (AGA), SGA (weight for
gestational age below the 10th percentile) or LGA (weight for gestational age above the 90th
percentile). Macrossomia is usually defined as a term birth weight above 4,000 g or 4,500 g.
Obese women who lost weight during pregnancy had lower absolute risk for LGA, but
higher absolute risk for SGA (27). For obese women, the proportion of SGA can increase with
every 1 kg weight loss during pregnancy (38). Adequate ranges of GWG associated with
minimal risks for LGA and SGA can differ across pre-pregnancy BMI groups in this high-risk
population.
Blomberg et al. assessed the effects of lower GWG and weight loss during pregnancy
on fetal growth (30). Compared with GWG between 5 to 9 kg, women with class I obesity
that lost weight had higher risk of SGA, while a gain of 0.1 to 4.9 kg was not related to
increased risk of SGA, LGA or macrosomia. Bodnar et al. took the 2009 IOM
recommendations as reference and found that a GWG of 2.2 kg to less than 5 kg for obesity
class III women was associated with a probability of less than 10% LGA and SGA births (14).
Hinkle et al. evaluated the risk for SGA, LGA, and macrosomia and suggested that a GWG
below the 2009 IOM guidelines could be associated with more adequate birth weight (15).
A pilot study evaluated retrospectively GWG in patients with obesity and type 2
diabetes in relation to fetal growth and perinatal morbidity (39). Patients with GWG below 5
kg (mean 3.7 kg) had lower rates of LGA, preterm delivery and perinatal morbidity compared
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to those with an average GWG of 12 kg, after adjusting for pre-gestational BMI. Catalano et.
al suggested that weight loss or even a lower than 5 kg gain in overweight or obese women
were associated with increased rates of SGA, with a negative effect on anthropometric birth
measures (40). However, results were not stratified according to obesity class.
Other fetal outcomes
Preterm delivery, fetal distress, Apgar score, shoulder dystocia, congenital anomalies and
childhood obesity have not yet been fully evaluated or were not evaluated at all regarding the
2009 IOM recommendations.
Preterm delivery, defined as before 37 weeks completed gestation, is a critical indicator
of fetal maturity and is directly associated with the risk of mortality and morbidity according
to the grade of prematurity (5). In obese women, an association of lower GWG with preterm
delivery remains uncertain. A longitudinal pre-birth cohort study in Massachusetts, the Project
Viva, investigated the rate of GWG associated with the lowest combined risk of five short and
longer-term maternal and child health outcomes (preterm delivery, maternal postpartum
weight retention, SGA, LGA, and child obesity at age 3 years) for 2,012 mother-child pairs
recruited in 1999–2002 (41). The lowest predicted outcome prevalence occurred with 0.19
kg/week loss for pregnant women with a pre-pregnancy BMI ≥30.0 kg/m² (41).
Fetal distress was evaluated in few studies of class I-III obese women with low GWG
or weight loss. It seems reasonably safe for obese women to gain a minimal weight with no
increased risk for most maternal and fetal adverse outcomes (13).
A low Apgar score, defined as less than 7 at 5 minutes, was evaluated in only two
observational studies (13, 32). Newborns of class I-III obese women with low GWG (0–5 kg)
did not markedly differ from newborns of obese women that gained weight according to the
2009 IOM recommendations.
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Maternal obesity appears to be associated with a small but independent increased risk
for fetal malformations including neural tube defects (NTD), cardiac anomalies, oro-facial
clefts, hydrocephaly, limb reduction anomalies as well as stillbirth and macrosomia (42).
Mechanisms linking congenital malformations to maternal obesity are not known, but they
could be related to an altered intrauterine nutritional milieu as well as to hyperinsulinemia
(43). Moreover, the protective effect of folic acid supplementation in reducing the risk of
NTD may not be observed in obese women (42). Unfortunately, prenatal screening of
malformations is significantly limited because maternal obesity can lessen the ultrasound
detection rate of fetal anomalies by at least 20% compared with women with a normal BMI
(44).
A number of observational studies have described an association between GWG above
the 2009 IOM recommendations and greater adiposity in the offspring (45). Preliminary
results suggest that a low GWG in obese women could attenuate childhood adiposity related
outcomes of the offspring. Recently, a retrospective study described the association of GWG
with offspring outcomes at an average age of 10.4 years (45). The effect of maternal pre-
pregnancy BMI on several childhood outcomes was attenuated in offsprings of mothers with
adequate vs excessive GWG. A suboptimal GWG conveys no benefit or risk on children's
overweight and abdominal adiposity as described in a retrospective cohort study in Germany
that investigated the interrelationship between inadequate or excessive GWG, according to
maternal pre-pregnancy BMI (46).
EFFECT OF WEIGHT LOSS DURING PREGNANCY
Weight loss during pregnancy can have short and long term repercussions for both
mother and fetus. Weight loss may be accompanied by ketonuria which effect on fetal and
child neurodevelopment remains uncertain. To assess whether prolonged fasting (13-18 hours
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per day) during the month of Ramada could cause ketonemia or ketonuria with significant
impact on intrauterine fetal development, a prospective study was conducted in Turkey (47).
Thirty six patients above 20 weeks of gestation of an uneventful pregnancy fasted for periods
of 18 days on average. At delivery, there were no significant differences in ultrasonographic
fetal measures or estimated fetal weight neither in maternal serum ketone bodies when
compared to non-fasting pregnant controls.
So far, no randomized trials of weight loss in obese pregnant women are available.
Observational studies favors the idea of weight loss in obese patients, as it seems to reduce
some obesity related complications during pregnancy at the expense of a potential higher risk
of a SGA birth (32). A retrospective analysis of more than 122,000 pregnancies from Atlanta
suggests that a weight loss up to 5 kg in class II-III obese women, conferred a favorable risk-
benefit profile without an increased risk of SGA (15). As previously cited, Blomberg et al.
found a reduction in the rates of cesarean delivery, preeclampsia and LGA, offset by an
increased risk of SGA in patients class II-III obesity who lost weight during pregnancy (13).
However, the authors argued that the twofold increase in risk of SGA birth (3.7%) in class III
obesity who lost weight is only slightly above the overall population prevalence in Sweden
(3.6%). More recently, Kominiarek et al. reported a risk for SGA infants in class I-III obese
women who lost an average -4.8 to -5.6 kg weight when compared to women with GWG
between 5 to 9 kg (32). The lowest average predicted probability of adverse outcomes
(cesarean delivery, postpartum hemorrhage, SGA, LGA birth, neonatal care unit admission)
occurred when class I-III obese pregnant women lost weight (up to 20 pounds).
PERSPECTIVES - Areas of uncertainty
Mechanisms by which body weight influences reproductive function and performance
are not well-understood and need further clarification (47). The effects of maternal BMI
status, insulin resistance, and inflammation on placental function and birth outcomes need to
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be examined in greater detail (47). Furthermore, research on the relationships of amount,
composition, and pattern of GWG for overweight, obese, and severely obese women related
to short and long term health outcomes for mother and child is much required.
It is not known whether a high maternal pre-pregnancy BMI contributes to an
intrauterine developmental programming process that increases the risk of childhood
overweight and long term disease, or whether the obesogenic environment of home and
family is the primary determinant of childhood obesity and subsequent diseases (47). Hence,
studies assessing the epigenetic mechanisms that underline and /or potentiate the effects of
GWG on fetal outcomes are needed (5). It is important to consider that current
recommendations for GWG are from American cohorts whose offspring´s weight was AGA.
These recommendations have not been adjusted for variables such as age, parity, smoking and
ethnicity. So it remains unanswered which optimal GWG is recommended according to
variables other than maternal pre-pregnancy BMI.
CONCLUSION
Evidence from observational studies published after the 2009 IOM guidelines
publication suggest that a lower GWG (0 - 5 kg) could influence LGA and SGA risks in
opposite directions, with decreased risk for LGA and increased risk for SGA mainly in
obesity classes I-II. It is important to emphasize that each obese BMI class consists of a
distinct population with different magnitude of baseline and pregnancy-related risks. It is
important to note that weight management should be primarily based on fetal growth, since
this was the most widely outcome assessed in all studies.
Validation of results from observational studies must come from intervention trials
with adequate statistical power to answer whether dietary intervention as well as physical
activity to induce lower GWG in obese women. However, even with the limitations of the
power of the available evidence, it seems urgent to review the recommendations on GWG,
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taking into account the class of obesity as well as the assessment of fetal growth for weight
gain goals during gestation.
Conflicts of Interest
The authors declare no conflicts of interest.
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