Emerging role of hypothalamus in the metabolic regulation in the offspring of maternal obesity

Maternal obesity has a significant impact on the metabolism of offspring both in childhood and adulthood. The metabolic regulation of offspring is influenced by the intrauterine metabolic programming induced by maternal obesity. Nevertheless, the precise mechanisms remain unclear. The hypothalamus is the primary target of metabolic programming and the principal regulatory center of energy metabolism. Accumulating evidence has indicated the crucial role of hypothalamic regulation in the metabolism of offspring exposed to maternal obesity. This article reviews the development of hypothalamus, the role of the hypothalamic regulations in energy homeostasis, possible mechanisms underlying the developmental programming of energy metabolism in offspring, and the potential therapeutic approaches for preventing metabolic diseases later in life. Lastly, we discuss the challenges and future directions of hypothalamic regulation in the metabolism of children born to obese mothers.

[1]  A. Lungkaphin,et al.  The programming of kidney injury in offspring affected by maternal overweight and obesity: role of lipid accumulation, inflammation, oxidative stress, and fibrosis in the kidneys of offspring , 2022, Journal of Physiology and Biochemistry.

[2]  S. Luquet,et al.  Hypothalamic astrocytes control systemic glucose metabolism and energy balance via regulation of extra-synaptic glutamate signaling , 2022, bioRxiv.

[3]  A. Loudon,et al.  Cryptochrome proteins regulate the circadian intracellular behavior and localization of PER2 in mouse suprachiasmatic nucleus neurons , 2022, Proceedings of the National Academy of Sciences.

[4]  J. Brüning,et al.  Maternal Metabolic Programming of the Developing Central Nervous System: Unified Pathways to Metabolic and Psychiatric Disorders , 2021, Biological Psychiatry.

[5]  A. Keller,et al.  Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice , 2021, bioRxiv.

[6]  J. Deem,et al.  AgRP neurons: Regulators of feeding, energy expenditure, and behavior , 2021, The FEBS journal.

[7]  R. Ensenauer,et al.  Influence of maternal and paternal pre-conception overweight/obesity on offspring outcomes and strategies for prevention , 2021, European Journal of Clinical Nutrition.

[8]  G. Yeo,et al.  Sirt3 in POMC neurons controls energy balance in a sex- and diet-dependent manner , 2021, Redox biology.

[9]  Jinhang Zhang,et al.  Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  D. Cota,et al.  POMC neuronal heterogeneity in energy balance and beyond: an integrated view , 2021, Nature Metabolism.

[11]  S. Bouret,et al.  Nutritional and developmental programming effects of insulin , 2021, Journal of neuroendocrinology.

[12]  M. Ferrini,et al.  Maternal High Fat Diet Programs Male Mice Offspring Hyperphagia and Obesity: Mechanism of Increased Appetite Neurons via Altered Neurogenic Factors and Nutrient Sensor AMPK , 2020, Nutrients.

[13]  S. Ozanne,et al.  Maternal obesity causes fetal hypothalamic insulin resistance and disrupts development of hypothalamic feeding pathways , 2020, Molecular metabolism.

[14]  S. Bouret,et al.  The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates , 2020, Nature Communications.

[15]  L. Velloso,et al.  Pro-opiomelanocortin (POMC) neuron translatome signatures underlying obesogenic gestational malprogramming in mice , 2020, Molecular metabolism.

[16]  Rohan M. Lewis,et al.  Maternal Obesity during Pregnancy Alters Daily Activity and Feeding Cycles, and Hypothalamic Clock Gene Expression in Adult Male Mouse Offspring , 2019, International journal of molecular sciences.

[17]  A. Oberthuer,et al.  Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring , 2019, Front. Neurosci..

[18]  A. Prentice,et al.  Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease , 2019, Frontiers in Neuroendocrinology.

[19]  T. Buchanan,et al.  Children Exposed to Maternal Obesity or Gestational Diabetes Mellitus During Early Fetal Development Have Hypothalamic Alterations That Predict Future Weight Gain , 2019, Diabetes Care.

[20]  S. Bouret,et al.  Maternal obesity-induced endoplasmic reticulum stress causes metabolic alterations and abnormal hypothalamic development in the offspring , 2019, bioRxiv.

[21]  M. Prinz,et al.  Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology. , 2019, Trends in molecular medicine.

[22]  J. Donato,et al.  SOCS3 as a future target to treat metabolic disorders , 2018, Hormones.

[23]  G. Pedrino,et al.  Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance. , 2018, The Journal of nutritional biochemistry.

[24]  K. Grove,et al.  Hypothalamic oxidative stress and inflammation, and peripheral glucose homeostasis in Sprague-Dawley rat offspring exposed to maternal and postnatal chocolate and soft drink , 2018, Nutrition & Diabetes.

[25]  A. Camacho,et al.  Maternal overnutrition by hypercaloric diets programs hypothalamic mitochondrial fusion and metabolic dysfunction in rat male offspring , 2018, Nutrition & Metabolism.

[26]  Anne White,et al.  Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats , 2018, International Journal of Obesity.

[27]  P. Vajro,et al.  Maternal Microbiota, Prepregnancy Weight, and Mode of Delivery: Intergenerational Transmission of Risk for Childhood Overweight and Obesity. , 2018, JAMA pediatrics.

[28]  C. Lotfi,et al.  SOCS3 expression in SF1 cells regulates adrenal differentiation and exercise performance. , 2017, The Journal of endocrinology.

[29]  B. Barres,et al.  Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility. , 2017, Cell metabolism.

[30]  L. Nguyen,et al.  Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus. , 2017, Journal of molecular endocrinology.

[31]  T. Powell,et al.  Effects of maternal obesity on placental function and fetal development. , 2017, Reproduction.

[32]  S. Diano,et al.  POMC Neurons: From Birth to Death. , 2017, Annual review of physiology.

[33]  J. Brüning,et al.  Hypothalamic inflammation in obesity and metabolic disease , 2017, The Journal of clinical investigation.

[34]  K. Godfrey,et al.  Influence of maternal obesity on the long-term health of offspring. , 2017, The lancet. Diabetes & endocrinology.

[35]  Dong Won Kim,et al.  Maternal obesity leads to increased proliferation and numbers of astrocytes in the developing fetal and neonatal mouse hypothalamus , 2016, International Journal of Developmental Neuroscience.

[36]  A. Weller,et al.  DNA CpG Methylation (5-Methylcytosine) and Its Derivative (5-Hydroxymethylcytosine) Alter Histone Posttranslational Modifications at the Pomc Promoter, Affecting the Impact of Perinatal Diet on Leanness and Obesity of the Offspring , 2016, Diabetes.

[37]  J. Betley,et al.  An Emerging Technology Framework for the Neurobiology of Appetite. , 2016, Cell metabolism.

[38]  S. Hitch.  From Birth to Death , 2015 .

[39]  S. Ozanne,et al.  Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis , 2015, Frontiers in Neuroendocrinology.

[40]  J. C. Diesel,et al.  Gestational weight gain and the risk of offspring obesity at 10 and 16 years: a prospective cohort study in low‐income women , 2015, BJOG : an international journal of obstetrics and gynaecology.

[41]  G. Liao,et al.  Brain-derived neurotrophic factor is required for axonal growth of selective groups of neurons in the arcuate nucleus , 2015, Molecular metabolism.

[42]  C. Knauf,et al.  Impact of hypothalamic reactive oxygen species in the regulation of energy metabolism and food intake , 2015, Front. Neurosci..

[43]  S. Bouret,et al.  Neonatal ghrelin programs development of hypothalamic feeding circuits. , 2015, The Journal of clinical investigation.

[44]  M. Benahmed,et al.  The offspring of the diabetic mother--short- and long-term implications. , 2015, Best practice & research. Clinical obstetrics & gynaecology.

[45]  H. Münzberg,et al.  Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat , 2015, Cell.

[46]  J. Elmquist,et al.  Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. , 2014, Cell metabolism.

[47]  R. Lane,et al.  Maternal obesity and high-fat diet program offspring metabolic syndrome. , 2014, American journal of obstetrics and gynecology.

[48]  A. Weller,et al.  Overweight and CpG methylation of the Pomc promoter in offspring of high‐fat‐diet‐fed dams are not “reprogrammed” by regular chow diet in rats , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  D. Cai,et al.  Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response , 2014, Nature Medicine.

[50]  L. Velloso,et al.  Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation. , 2014, Metabolism: clinical and experimental.

[51]  Guowei Huang,et al.  Maternal high-fat diet affects Msi/Notch/Hes signaling in neural stem cells of offspring mice. , 2014, The Journal of nutritional biochemistry.

[52]  T. Horvath,et al.  Neonatal Insulin Action Impairs Hypothalamic Neurocircuit Formation in Response to Maternal High-Fat Feeding , 2014, Cell.

[53]  G. Yeo,et al.  The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis. , 2013, Current opinion in pharmacology.

[54]  M. Dietrich,et al.  Mitofusin 2 in POMC Neurons Connects ER Stress with Leptin Resistance and Energy Imbalance , 2013, Cell.

[55]  J. Brüning,et al.  Perinatal programming of metabolic diseases: role of insulin in the development of hypothalamic neurocircuits. , 2013, Endocrinology and metabolism clinics of North America.

[56]  K. Gohil,et al.  Maternal obesity affects gene expression and cellular development in fetal brains , 2013, Nutritional neuroscience.

[57]  S. Bouret,et al.  Nutritional programming of hypothalamic development: critical periods and windows of opportunity. , 2012, International journal of obesity supplements.

[58]  J. Argente,et al.  Emerging role of glial cells in the control of body weight. , 2012, Molecular metabolism.

[59]  A. Saito,et al.  Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue , 2012, Scientific Reports.

[60]  A. Bruce-Keller,et al.  Saturated long‐chain fatty acids activate inflammatory signaling in astrocytes , 2012, Journal of neurochemistry.

[61]  S. Padilla,et al.  Defining POMC neurons using transgenic reagents: impact of transient Pomc expression in diverse immature neuronal populations. , 2012, Endocrinology.

[62]  S. Bouret,et al.  Distinct Roles for Specific Leptin Receptor Signals in the Development of Hypothalamic Feeding Circuits , 2012, The Journal of Neuroscience.

[63]  Michael L. Blackburn,et al.  Maternal obesity promotes a proinflammatory signature in rat uterus and blastocyst. , 2011, Endocrinology.

[64]  Chase R Figley,et al.  Lactate Transport and Metabolism in the Human Brain: Implications for the Astrocyte-Neuron Lactate Shuttle Hypothesis , 2011, The Journal of Neuroscience.

[65]  Haiyan Xu,et al.  FFA‐Induced Adipocyte Inflammation and Insulin Resistance: Involvement of ER Stress and IKKβ Pathways , 2011, Obesity.

[66]  E. Ropelle,et al.  Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. , 2011, Endocrinology.

[67]  F. Guillemot,et al.  Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus. , 2011, Developmental biology.

[68]  S. Bouret.  Neurodevelopmental actions of leptin , 2010, Brain Research.

[69]  S. Padilla,et al.  Pomc-expressing progenitors give rise to antagonistic populations in hypothalamic feeding circuits , 2010, Nature Medicine.

[70]  M. Fortini,et al.  Notch signaling: the core pathway and its posttranslational regulation. , 2009, Developmental cell.

[71]  M. Karin,et al.  Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity , 2008, Cell.

[72]  B. Lowell,et al.  Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance , 2008, Nature Neuroscience.

[73]  Tamas L. Horvath,et al.  UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals , 2008, Nature.

[74]  S. Tobet,et al.  GABAB receptors role in cell migration and positioning within the ventromedial nucleus of the hypothalamus , 2008, Neuroscience.

[75]  M. Sena-Esteves,et al.  Selective Deletion of Bdnf in the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity , 2007, The Journal of Neuroscience.

[76]  S. Matsuda,et al.  Microglia‐derived interleukin‐6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells , 2007, The European journal of neuroscience.

[77]  F. Guillemot,et al.  Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells. , 2006, Molecular endocrinology.

[78]  S. Bouret,et al.  Formation of Projection Pathways from the Arcuate Nucleus of the Hypothalamus to Hypothalamic Regions Implicated in the Neural Control of Feeding Behavior in Mice , 2004, The Journal of Neuroscience.

[79]  E. H. Goulding,et al.  Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor , 2003, Nature Neuroscience.

[80]  George Paxinos,et al.  Organization of human hypothalamus in fetal development , 2002, The Journal of comparative neurology.

[81]  T. Ohtsuka,et al.  The Notch-Hes pathway in mammalian neural development , 1999, Cell Research.

[82]  L. Renaud,et al.  Ultrastructural evidence for intra‐ and extranuclear projections of GABAergic neurons of the suprachiasmatic nucleus , 1994, The Journal of comparative neurology.

[83]  Ruth E. Hartley,et al.  An integrated view. , 1973 .