Rap1 in the VMH regulates glucose homeostasis

Abstract

The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet (HFD)-induced obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in SF1-positive neurons in the ventromedial hypothalamic nucleus (VMH) known to regulate glucose metabolism. While having no effect on body weight regardless of sex, diet, and age, Rap1 deficiency in the VMH SF1 neurons markedly lowered blood glucose and insulin levels, improved glucose and insulin tolerance, and protected mice against HFDinduced neural leptin resistance and peripheral insulin resistance at the cellular and whole-body levels. Lastly, acute pharmacological inhibition of brain EPAC2, a direct activator of Rap1, corrected glucose imbalance in obese mouse models. Our findings uncover the primary role of VMH Rap1 in glycemic control and implicate Rap1 signaling as a potential target for therapeutic intervention in diabetes.

Marker genes of incident type 1 diabetes in peripheral blood mononuclear cells of children: A machine learning strategy for large-p, small-n scenarios

“…Our findings on the marker genes of incident T1D were congruent with previous studies which reported an innate inflammatory transcriptomic profile characterized by perturbations of genes such as CSDE1, EGR2, FRAT2, GNG11, IL1B, PTP4A2, SLC35A3, and UCHL3 [17,43]. Moreover, there is topical evidence that RAP1B regulates glucose homeostasis [44], while the dysregulation of protein tyrosine phosphatases such as PTP4A2 (PRL2) is observed in several diabetes phenotypes [45]. Both MICA and MICB candidate genes belong to the HLA complex, which is collectively and consistently associated with T1D, contributing to 50% of its genetic risk [6].…”

Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity

“…Previous studies have greatly expanded our knowledge of the CNS control of metabolism, including energy balance and glucose homeostasis (2,4). It is of increasing interest to identify molecular players, signaling pathways, and neurocircuits involved as potential therapeutic targets to treat obesity and diabetes (12,16,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). Our findings have identified an antiobesogenic role of OGT in the VMH control of metabolism (Fig.…”

The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis

“…[ 129 ]). In addition, most recent studies suggested that Rap1 and prostaglandin in the VMH have also been implicated into glucose homeostasis [ 123 , 128 ].…”

“…Encoded by Rap1a and Rap1b , Rap1 is a small GTPase that is expressed throughout the whole body including the brain [ 130 ]. We have shown that increasing Rap1 activity in VMH SF1 neurons elevates blood glucose without alteration of body weight; ablation of Rap1 in VMH SF1 neurons remarkedly lowers blood glucose, improves both glucose tolerance and insulin sensitivity in high fat diet (HFD)-fed mice [ 123 ]. Work from Lee and colleagues has demonstrated that a glucose injection elicits a reduction in arachidonic-acid-containing phospholipids concomitant with an increase of prostaglandin production derived from phospholipids in the VMH [ 128 ].…”