STAT5 ablation in AgRP neurons increases female adiposity and blunts food restriction adaptations

Abstract

AgRP neurons are important players in the control of energy homeostasis and are responsive to several hormones. In addition, STAT5 signalling in the brain, which is activated by metabolic hormones and growth factors, modulates food intake, body fat and glucose homeostasis. Given that, and the absence of studies that describe STAT5 function in AgRP cells, the present study investigated the metabolic effects of Stat5a/b gene ablation in these neurons. We observed that STAT5 signalling in AgRP neurons regulates body fat in female mice. However, male and female STAT5-knockout mice did not exhibit altered food intake, energy expenditure or glucose homeostasis compared to control mice. The counter-regulatory response or glucoprivic hyperphagia induced by 2-deoxy-d-glucose treatment were also not affected by AgRP-specific STAT5 ablation. However, under 60% food restriction, AgRP STAT5-knockout mice had a blunted upregulation of hypothalamic Agrp mRNA expression and corticosterone serum levels compared to control mice, suggesting a possible role for STAT5 in AgRP neurons for neuroendocrine adaptations to food restriction. Interestingly, ad libitum fed knockout male mice had reduced Pomc and Ucp-1 mRNA expression compared to control group. Taken together, these results suggest that STAT5 signalling in AgRP neurons regulates body adiposity in female mice, as well as some neuroendocrine adaptations to food restriction.

Growth hormone receptor in dopaminergic neurones regulates stress‐induced prolactin release in male mice

“…Growth hormone-responsive neurones were identified in the present study via the expression of pSTAT5 in mice previously injected with GH. Although this method has been extensively used by our research group, 13,[15][16][17][18][19][29][30][31][40][41][42][43] we cannot guarantee that all pSTAT5 positive cells express GHR. Indeed, no study so far has demonstrated that TIDA neurones express Ghr mRNA.…”

“…15,[17][18][19][29][30][31]40 These studies revealed that GH has a particularly important action during situations of stress or when homeostasis is challenged. 41 For example, during food deprivation, GHR signalling in AgRP-expressing neurones triggers energy-saving adaptations to decrease weight loss and increase the chances of survival, 15,16 whereas, during hypoglycaemia, GH action on VMH neurones enhances the counter-regulatory response to recover blood glucose levels. 30 Interestingly, in most of the cases, GHR ablation in specific neuronal populations caused no or just minor physiological changes during basal conditions, 15,17,29,30 highlighting the impor- TH-specific GHR knockout mice that is secondary to increased GH secretion, as previously demonstrated.…”

“…Recent studies have investigated possible physiological roles played by GH in specific ARH neurones. GH action on ARH agouti‐related peptide (AgRP)‐producing neurones regulates metabolic and neuroendocrine adaptations trigged during food restriction, 15 partially via STAT5‐dependent mechanisms 16 . GHR expression in pro‐opiomelanocortin‐expressing cells is required for the hyperphagia induced during glucoprivic situations 17 .…”

“…GH action on ARH agouti-related peptide (AgRP)-producing neurones regulates metabolic and neuroendocrine adaptations trigged during food restriction, 15 partially via STAT5-dependent mechanisms. 16 GHR expression in pro-opiomelanocortin-expressing cells is required for the hyperphagia induced during glucoprivic situations. 17 By contrast, ARH kisspeptinproducing neurones do not exhibit GH-induced STAT5 phosphorylation (pSTAT5), suggesting that these cells do not express GHR.…”

Effects of Growth Hormone Receptor Ablation in Corticotropin-Releasing Hormone Cells

“…These areas include the arcuate nucleus (ARH), ventromedial nucleus (VMH), paraventricular nucleus of the hypothalamus (PVH), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CEA) and locus coeruleus [ 25 , 26 ]. In the ARH, GH acts in several distinct neuronal populations, such as neurons that express agouti-related protein (AgRP) [ 11 , 23 , 27 , 28 , 29 , 30 ], proopiomelanocortin (POMC) [ 31 ], tyrosine hydroxylase [ 32 , 33 ] or choline acetyltransferase [ 34 ]. The role of GHR signaling in these neuronal populations is starting to be unraveled.…”