Temporary effects of neonatal overfeeding on homeostatic control of food intake involve alterations in POMC promoter methylation in male rats

Schumacher, Rocío; Rossetti, María Florencia; Lazzarino, Gisela Paola; Canesini, Guillermina; García, Ana Paula; Stoker, Cora; Andreoli, María Florencia; Ramos, Jorge G.

doi:10.1016/j.mce.2020.111123

Cited by 9 publications

(11 citation statements)

References 48 publications

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“…Anorexigenic neuropeptides, located in the mediobasal hypothalamus, such as proopiomelanocortin (POMC), and melanocortin-4 receptor (MC4R), mediate satiety and increase energy expenditure, thus lead to loss of weight (13)(14)(15). Several studies have focused on the effects of maternal over-nutrition on hypothalamic neuropeptides, with increased expressions of POMC and MC4R in offspring (16)(17)(18). However, little information is known about the mechanisms linking prenatal LP and postnatal HF diets with altered expression of brain neurotransmitters, and investigations into the epigenetic modification of hypothalamus in offspring are limited.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice

et al. 2021

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Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = −0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.

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Section: Introductionmentioning

confidence: 99%

Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice

et al. 2021

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“…Many studies have reported that overnutrition during lactation in rodents not only results in several metabolic disorders but also in cardiovascular alterations that include cardiac dysfunction and the development of hypertension [24][25][26]. The metabolic changes associated with postnatal overfeeding have been widely described [27] and are due to alterations both in the central systems involved in food intake regulation [28][29][30][31] and in peripheral tissues involved in metabolism such as the gastrointestinal system, the liver, and the adipose tissue [32,33]. In this regard, our results agree with previous studies, which have reported that early overnutrition is associated with increased body weight at weaning, which is maintained in adulthood [22,34,35].…”

Section: Discussionmentioning

confidence: 99%

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats

Tejera-Muñoz,

Guerra-Menéndez,

Amor

et al. 2023

IJMS

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Early overnutrition is associated with cardiometabolic alterations in adulthood, likely attributed to reduced insulin sensitivity due to its crucial role in the cardiovascular system. This study aimed to assess the long-term effects of early overnutrition on the development of cardiovascular insulin resistance. An experimental childhood obesity model was established using male Sprague Dawley rats. Rats were organized into litters of 12 pups/mother (L12-Controls) or 3 pups/mother (L3-Overfed) at birth. After weaning, animals from L12 and L3 were housed three per cage and provided ad libitum access to food for 6 months. L3 rats exhibited elevated body weight, along with increased visceral, subcutaneous, and perivascular fat accumulation. However, heart weight at sacrifice was reduced in L3 rats. Furthermore, L3 rats displayed elevated serum levels of glucose, leptin, adiponectin, total lipids, and triglycerides compared to control rats. In the myocardium, overfed rats showed decreased IL-10 mRNA levels and alterations in contractility and heart rate in response to insulin. Similarly, aortic tissue exhibited modified gene expression of TNFα, iNOS, and IL-6. Additionally, L3 aortas exhibited endothelial dysfunction in response to acetylcholine, although insulin-induced relaxation remained unchanged compared to controls. At the molecular level, L3 rats displayed reduced Akt phosphorylation in response to insulin, both in myocardial and aortic tissues, whereas MAPK phosphorylation was elevated solely in the myocardium. Overfeeding during lactation in rats induces endothelial dysfunction and cardiac insulin resistance in adulthood, potentially contributing to the cardiovascular alterations observed in this experimental model.

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“…Studies have demonstrated that neonatally overfed rats have a hyperreactive hypothalamus-pituitary-adrenal (HPA) axis, accompanied by elevated stress-induced corticosterone levels in adulthood, suggesting that these modifications may play a role in anxiety-related behaviour [ 8 , 30 , 38 ]. NPY1R plays a significant role in the regulation of the HPA axis [ 40 ]. However, little is known about the role of NPY signalling in mediating metabolic and neuronal changes.…”

Section: Discussionmentioning

confidence: 99%

“…Limbic neuropeptide Y1R may be a possible mechanism related to postnatal metabolic and behavioural changes. Studies have demonstrated that during weaning, male offspring from the SL group presented an increased expression of POMC, NPY, and ghrelin (GHS-R1α) receptor in the ARC hypothalamic region, which contributes to satiety control dysregulation [ 40 , 41 ]. On the other hand, NPY1R has a strong effect in suppressing neurons located in the ventromedial nucleus of the hypothalamus, suggesting that NPY1R may have a different role according to its hypothalamic region [ 5 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Postnatal Overfeeding in Rodents Induces a Neurodevelopment Delay and Anxious-like Behaviour Accompanied by Sex- and Brain-Region-Specific Synaptic and Metabolic Changes

et al. 2023

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Nutritional disturbances during the early postnatal period can have long-lasting effects on neurodevelopment and may be related to behavioural changes at adulthood. While such neuronal connection disruption can contribute to social and behaviour alterations, the dysregulation of the neuroendocrine pathways involved in nutrient-sensing balance may also cause such impairments, although the underlying mechanisms are still unclear. We aimed to evaluate sex-specific neurodevelopmental and behavioural changes upon postnatal overfeeding and determine the potential underpinning mechanisms at the central nervous system level, with a focus on the interconnection between synaptic and neuroendocrine molecular alterations. At postnatal day 3 (PND3) litters were culled to three animals (small litter procedure). Neurodevelopmental tests were conducted at infancy, whereas behavioural tests to assess locomotion, anxiety, and memory were performed at adolescence, together with molecular analysis of the hippocampus, hypothalamus, and prefrontal cortex. At infancy, females presented impaired acquisition of an auditory response, eye opening, olfactory discrimination, and vestibular system development, suggesting that female offspring neurodevelopment/maturation was deeply affected. Male offspring presented a transitory delay in locomotor performance., while both offspring had lower upper limb strength. At adolescence, both sexes presented anxious-like behaviour without alterations in short-term memory retention. Both males and females presented lower NPY1R levels in a region-specific manner. Furthermore, both sexes presented synaptic changes in the hippocampus (lower GABAA in females and higher GABAA levels in males), while, in the prefrontal cortex, similar higher GABAA receptor levels were observed. At the hypothalamus, females presented synaptic changes, namely higher vGLUT1 and PSD95 levels. Thus, we demonstrate that postnatal overfeeding modulates offspring behaviour and dysregulates nutrient-sensing mechanisms such as NPY and GABA in a sex- and brain-region-specific manner.

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Temporary effects of neonatal overfeeding on homeostatic control of food intake involve alterations in POMC promoter methylation in male rats

Cited by 9 publications

References 48 publications

Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice

Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats

Postnatal Overfeeding in Rodents Induces a Neurodevelopment Delay and Anxious-like Behaviour Accompanied by Sex- and Brain-Region-Specific Synaptic and Metabolic Changes

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