Perinatal free‐choice of a high‐calorie low‐protein diet affects leptin signaling through IRS1 and AMPK dephosphorylation in the hypothalami of female rat offspring in adulthood

Abstract

Aim We aimed to investigate whether a dysregulated maternal diet during gestation and lactation induces long‐lasting changes in the hypothalamic control of feeding behavior in the offspring and whether this effect is sex specific. Methods The study included an analysis of appetite‐regulating metabolic hormones and hypothalamic signaling in male and female offspring in adulthood after exposure to a free‐choice high‐calorie palatable low‐protein (P) diet or standard chow (C) during (pre)gestation/lactation (maternal) and/or postweaning (offspring). Results Maternal exposure to the P diet resulted in decreased protein intake and body weight gain in dams and decreased body weight gain in offspring during lactation. The maternal P diet (PC) specifically increased feed efficacy and decreased body weight and cholesterol levels in the female offspring in adulthood, but no changes in adiposity or leptin levels were found. In contrast, P diet exposure after weaning (CP and PP) increased caloric intake, adiposity and circulating levels of leptin in the male and female offspring in adulthood. The hypothalami of the female offspring exposed to the maternal P diet (PC and PP) expressed high levels of the phospho‐leptin receptor and low levels of SOCS3, phospho‐IRS1 and phospho‐AMPK, regardless of the postweaning diet. The hypothalami of the female rats in the PC group also showed increased levels of STAT3 and the orexigenic neuropeptide Agrp. Conclusions Maternal exposure to a free‐choice high‐calorie low‐protein diet induces a long‐term feed efficacy associated with changes in leptin signaling through IRS‐1 and AMPK dephosphorylation in the hypothalami of female offspring in adulthood.

Sex-Specific Anxiety and Prefrontal Cortex Glutamatergic Dysregulation Are Long-Term Consequences of Pre-and Postnatal Exposure to Hypercaloric Diet in a Rat Model

“…Traditionally, maternal nutrition studies have focused on offspring metabolic diseases, such as glucose tolerance, insulin resistance, dyslipidaemia, hypertension and obesity, in humans and rodents [ 4 , 30 , 31 ]. However, it is known that continued stress, such as malnutrition with an excess or deficiency in most nutrients, impacting fetal neurodevelopment, can cause neuropsychiatric disorders, including depression, anxiety and attention-deficit/hyperactivity disorder in offspring, even though to adulthood [ 32 ].…”

“…Maternal nutrition plays a crucial role in the offspring’s brain development during pregnancy and during a critical period after birth. Initial studies on perinatal programming have shown that malnutrition during pregnancy and/or lactation induces metabolic disorders such as hyperphagia, adiposity, hyperlipidemia and glucose intolerance in offspring, even into adulthood [ 1 , 2 , 3 , 4 ]. Moreover, growing evidence has revealed a modulation of the offspring behavior related to depression, anxiety-like behaviors and addiction (preference of hypercaloric foods and drugs) due to the consumption of a hypercaloric diet in the perinatal period, being associated with long-term structural and functional alterations in the neurodevelopment of the prefrontal cortex (PFC) [ 5 , 6 , 7 , 8 ].…”

A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse

“…We performed real-time PCR (TaqMan, ThermoFisher Scientific, Waltham, MA, USA) as described previously [107] using specific sets of primer probes from TaqMan ® Gene Expression Assays, as shown in Table S1. Total RNA was extracted from tibia samples using the Trizol ® method according to the manufacturer's instructions (ThermoFisher Scientific).…”

Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming

“…The alterations induced by nutritional programming in the hypothalamus of offspring are of special relevance given the important role of this brain region in energy homeostasis, appetite and body composition. Maternal malnutrition during the pre/gestational period can affect many hypothalamic signaling systems controlling appetite and energy expenditure [8][9][10]. One of them is the endocannabinoid system, which is involved in numerous functions both in development and adult life, highlighting energy metabolism, feeding behavior, emotional control and neurodegenerative diseases [11][12][13][14][15].…”