Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

Abstract

26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

Acute but Not Chronic Central Administration of the Neuropeptide 26RFa (QRFP) Improves Glucose Homeostasis in Obese/Diabetic Mice

“…However, we observed that, in these HF mice, central INS administration was not able to promote 26RFa hypothalamic expression, whereas we previously found that, in euglycemic mice, brain INS induced hypothalamic 26RFa expression and secretion during a glucose load [26]. In the same study, we also promoted the evidence that the 26RFa/GPR103 neuronal system mediates the central antihyperglycemic effect of INS [26].…”

“…In the present study, we show for the first time that an acute central administration of 26RFa in HF mice is still able to attenuate glucose-induced hyperglycemia by enhancing GSIS. This favorable central effect of 26RFa on INS secretion in this hyperglycemic model is therefore preserved and very similar in terms of amplitude and kinetic to that observed in euglycemic mice [26]. The dose we used for the acute i.c.v.…”

“…However, we observed that, in these HF mice, central INS administration was not able to promote 26RFa hypothalamic expression, whereas we previously found that, in euglycemic mice, brain INS induced hypothalamic 26RFa expression and secretion during a glucose load [26]. In the same study, we also promoted the evidence that the 26RFa/GPR103 neuronal system mediates the central antihyperglycemic effect of INS [26]. Altogether, these observations support the idea that the inability of INS to trigger the 26RFa/GPR103 system in hyperglycemic condition is an additional consequence of the well-known central INS resistance observed in obesity/diabetes and probably participates to the glucose intolerance developed by the HF mice.…”

“…However in obese/diabetic mice, the antihyperglycemic effect of 26RFa is significantly blunted due, at least in part, to a decreased expression of its receptor (GPR103) both in beta cells and in INS target tissues such as the adipose tissue and the muscles [25]. More recently, we found that the 26RFa neuronal system of the hypothalamus was also able to promote GSIS and could be considered as a mediator for central INS effects on glucose tolerance [26]. With regard to these recent data, we thought important to evaluate the central effect of the 26RFa on glucose metabolism in a diabetogenic context.…”

“…Finally, we promoted, very recently, the evidence that the 26RFa neuronal system of the hypothalamus plays a key role in the central regulation of glucose homeostasis by lowering glucose-induced hyperglycemia and by mediating central INS-induced peripheral INS secretion [26]. With regard to all of these observations, the aim of the present study was to investigate whether acute or chronic central administration of 26RFa may ameliorate the glycemic control of obese/diabetic mice.…”