RESUMO
Maternal overnutrition during lactation predisposes offspring to develop metabolic diseases and exacerbates the relevant syndromes in males more than females in later life. The hypothalamus is a heterogenous brain region that regulates energy balance. Here we combined metabolic trait quantification of mother and offspring mice under low and high fat diet (HFD) feeding during lactation, with single nucleus transcriptomic profiling of their offspring hypothalamus at peak lacation to understand the cellular and molecular alterations in response to maternal dietary pertubation. We found significant expansion in neuronal subpopulations including histaminergic (Hdc), arginine vasopressin/retinoic acid receptor-related orphan receptor ß (Avp/Rorb) and agouti-related peptide/neuropeptide Y (AgRP/Npy) in male offspring when their mothers were fed HFD, and increased Npy-astrocyte interactions in offspring responding to maternal overnutrition. Our study provides a comprehensive offspring hypothalamus map at the peak lactation and reveals how the cellular subpopulations respond to maternal dietary fat in a sex-specific manner during development.
Assuntos
Gorduras na Dieta , Obesidade , Humanos , Feminino , Camundongos , Masculino , Animais , Gorduras na Dieta/metabolismo , Obesidade/metabolismo , Hipotálamo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Neuropeptídeo Y/metabolismo , Lactação , Perfilação da Expressão Gênica , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
Caloric restriction is a robust intervention to increase lifespan. Giving less food (calorie restriction [CR]) or allowing free access to a diluted diet with indigestible components (calorie dilution [CD]) are two methods to impose restriction. CD does not generate the same lifespan effect as CR. We compare responses of C57BL/6 mice with equivalent levels of CR and CD. The two groups have different responses in fat loss, circulating hormones, and metabolic rate. CR mice are hungrier, as assessed by behavioral assays. Although gene expression of Npy, Agrp, and Pomc do not differ between CR and CD groups, CR mice had a distinctive hypothalamic gene-expression profile with many genes related to starvation upregulated relative to CD. While both result in lower calorie intake, CR and CD are not equivalent procedures. Increased hunger under CR supports the hypothesis that hunger signaling is a key process mediating the benefits of CR.
Assuntos
Restrição Calórica , Ingestão de Energia , Tecido Adiposo , Animais , Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: Maternal high-fat diet (HFD) increases offspring obesity, yet the impacts of different levels of maternal dietary fat have seldom been addressed. In mice, the impact of graded maternal dietary fat on offspring adiposity and offspring's later susceptibility to HFD were assessed. METHODS: Lactating mice were fed diets with graded fat content from 8.3% to 66.6%. One male and one female pup from each litter were weaned onto a low-fat diet for 15 weeks. HFD (41.7%) was then introduced to half of the offspring for 12 weeks. RESULTS: Offspring body weight and adiposity were positively related to maternal dietary fat content and were higher when mothers were exposed to HFD. The maternal diet effect was nonlinear and sex dependent. A maternal dietary fat of 41.7% and above exaggerated the offspring body weight gain in males but was not significant in females. Maternal 8.3% fat and 25% fat diets led to the highest daily energy expenditure and respiratory exchange ratio in offspring. Offspring fed a low-fat diet had higher daily energy expenditure and respiratory exchange ratio than those fed an HFD. CONCLUSIONS: Increasing maternal dietary fat during lactation, and HFD in later life, had significant and interacting impacts on offspring obesity. Maternal diet had a bigger impact on male offspring. The effects of maternal dietary fat content were nonlinear.
Assuntos
Adiposidade , Dieta Hiperlipídica , Gorduras na Dieta , Lactação , Fenômenos Fisiológicos da Nutrição Materna , Obesidade , Animais , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/análise , Suscetibilidade a Doenças , Metabolismo Energético , Feminino , Masculino , Camundongos , Obesidade/etiologia , Fatores SexuaisRESUMO
Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.
Assuntos
Tecido Adiposo Marrom/metabolismo , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Antibacterianos/administração & dosagem , Ceco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Termogênese/fisiologia , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.
Assuntos
Dieta com Restrição de Proteínas , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Ingestão de Alimentos , Metabolismo Energético , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Teste de Tolerância a Glucose , Hiperfagia/tratamento farmacológico , Hipotálamo/metabolismo , Leptina/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Redução de PesoRESUMO
The heat dissipation limit theory predicts that lactating female mice consuming diets with lower specific dynamic action (SDA) should have enhanced lactation performance. Dietary fat has lower SDA than other macronutrients. Here we tested the effects of graded dietary fat levels on lactating Swiss mice. We fed females five diets varying in fat content from 8.3 to 66.6%. Offspring of mothers fed diets of 41.7% fat and above were heavier and fatter at weaning compared with those of 8.3 and 25% fat diets. Mice on dietary fat contents of 41.7% and above had greater metabolizable energy intake at peak lactation (8.3%: 229.4±39.6; 25%: 278.8±25.8; 41.7%: 359.6±51.5; 58.3%: 353.7±43.6; 66.6%: 346±44.7â kJâ day-1), lower daily energy expenditure (8.3%: 128.5±16; 25%: 131.6±8.4; 41.7%: 124.4±10.8; 58.3%: 115.1±10.5; 66.6%: 111.2±11.5â kJâ day-1) and thus delivered more milk energy to their offspring (8.3%: 100.8±27.3; 25%: 147.2±25.1; 41.7%: 225.1±49.6; 58.3%: 238.6±40.1; 66.6%: 234.8±41.1â kJâ day-1). Milk fat content (%) was unrelated to dietary fat content, indicating that females on higher fat diets (>41.7%) produced more rather than richer milk. Mothers consuming diets with 41.7% fat or above enhanced their lactation performance compared with those on 25% or less, probably by diverting dietary fat directly into the milk, thereby avoiding the costs of lipogenesis. At dietary fat contents above 41.7% they were either unable to transfer more dietary fat to the milk, or they chose not to do so, potentially because of a lack of benefit to the offspring that were increasingly fatter as maternal dietary fat increased.