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Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.

ABSTRACT: Early life nutrition can reprogram development and exert long-term consequences on body weight regulation. In mice, maternal high-fat diet (HFD) during lactation predisposed male but not female offspring to diet-induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex-differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro-opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex-dependent susceptibility to obesity in adult life in mice.

SUBMITTER: Xu Y

PROVIDER: S-EPMC10724448 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.

Xu Yanchao Y Yang Dengbao D Wang Lu L Król Elżbieta E Mazidi Mohsen M Li Li L Huang Yi Y Niu Chaoqun C Liu Xue X Lam Sin Man SM Shui Guanghou G Douglas Alex A Speakman John R JR

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231022 35

Early life nutrition can reprogram development and exert long-term consequences on body weight regulation. In mice, maternal high-fat diet (HFD) during lactation predisposed male but not female offspring to diet-induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex-differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic ...[more]

PMID: 37867217

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Project description:The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high-fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single-minded family basic helix-loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane-bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1-Cre:Rosa-mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1-Cre:Rosa-mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1-Cre:Rosa-mEGFP male mice, there was decreased alpha-melanocyte-stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Project description:BackgroundDuration of breastfeeding is positively associated with decreased adiposity and increased metabolic health in later life, which might be related to galactose.ObjectiveThe aim of this study was to investigate if partial replacement of glucose with galactose in the postweaning diet had a metabolic programming effect.MethodsMale and female mice (C57BL/6JRccHsd) received an isocaloric diet (16 energy% fat; 64 energy% carbohydrates; 20 energy% protein) with either glucose (32 energy%) (GLU) or glucose + galactose (GLU + GAL, 16 energy% each) for 3 wk postweaning. Afterwards, all mice were switched to the same 40 energy% high-fat diet (HFD) for 9 wk to evaluate potential programming effects in an obesogenic environment. Data were analyzed within sex.ResultsFemale body weight (-14%) and fat mass (-47%) were significantly lower at the end of the HFD period (both P < 0.001) among those fed GLU + GAL than among those fed GLU; effects in males were in line with these findings but nonsignificant. Food intake was affected in GLU + GAL-fed females (+8% on postweaning diet, -9% on HFD) compared with GLU-fed females, but not for hypothalamic transcript levels at endpoint. Also, in GLU + GAL-fed females, serum insulin concentrations (-48%, P < 0.05) and the associated homeostasis model assessment of insulin resistance (HOMA-IR) were significantly lower ( P < 0.05) at endpoint, but there were no changes in pancreas morphology. In GLU + GAL-fed females, expression of insulin receptor substrate 2 (Irs2) (-27%, P < 0.01 ; -44%, P < 0.001) and the adipocyte size markers leptin (Lep) (-40%, P < 0.05; -63% , P < 0.05) and mesoderm-specific transcript homolog protein (Mest) (-80%, P < 0.05; -72%, P < 0.05) was lower in gonadal and subcutaneous white adipose tissue (WAT), respectively. Expression of insulin receptor substrate1 (Irs1) (-24%, P < 0.05) was only lower in subcutaneous WAT in GLU + GAL-fed females.ConclusionsPartial replacement of glucose with galactose, resulting in a 1:1 ratio mimicking lactose, in a 3-wk postweaning diet lowered body weight, adiposity, HOMA-IR, and expression of WAT insulin signaling in HFD-challenged female mice in later life. This suggests that prolonged galactose intake may improve metabolic and overall health in later life.

Dataset Information

Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.

Publications

Maternal High Fat Diet in Lactation Impacts Hypothalamic Neurogenesis and Neurotrophic Development, Leading to Later Life Susceptibility to Obesity in Male but Not Female Mice.

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