Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders

Abstract

The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.

Endoplasmic Reticulum–Plasma Membrane Contact Sites: Regulators, Mechanisms, and Physiological Functions

“…Studies of those proteins in specific tissues will be a way to identify their physiological roles. Recent studies have already confirmed this possibility (Guo et al, 2017 ; Kirmiz et al, 2018a ; Zhang et al, 2020 ). On the other hand, some regulators' functions are not related to ER-PM contact sites (Tremblay et al, 2016 ; El Kasmi et al, 2018 ).…”

“…However, E-Syts and tricalbins do have physiological effects. For example, E-Syts can maintain PM lipid homeostasis, promote nerve transmission and synaptic growth, modulate virus-induced membrane fusion, mediate the endocytosis of FGFR, and play roles in insulin secretion and diet-induced obesity development (Saheki et al, 2016 ; Tremblay et al, 2016 ; Kikuma et al, 2017 ; El Kasmi et al, 2018 ; Xie et al, 2019 ; Nath et al, 2020 ; Zhang et al, 2020 ). Tricalbins act in maintaining PM integrity (Toulmay and Prinz, 2012 ; Collado et al, 2019 ).…”

Metabolic Consequences of Neuronal HIF1α-Deficiency in Mediobasal Hypothalamus in Mice

“…Mice were anesthetized by intraperitoneal injection of 4% chloral hydrate (0.13 ml/10 g) for all surgeries. After virus injection, up to five mice were kept in one cage on chow diet (9.4% kcal from fat) ( 11 ), and cages were changed twice a week. The daily food intake of mice is calculated by cage: the total food intake of the cage/the number of mice.…”

Deficiency of ER Ca2+ sensor STIM1 in AgRP neurons confers protection against dietary obesity

“…Several neuronal subsets, including agouti-related peptide (AgRP)-producing neurons, are implicated in this process (Gautron et al, 2015;Morton et al, 2014). Previous work has identified various molecules and pathways, including PTP1b (Bence et al, 2006), IKKb (Zhang et al, 2008), ER stress (Ozcan et al, 2009;Zhang et al, 2008), JNK1 (Belgardt et al, 2010), GABA (g-aminobutyric acid) (Vong et al, 2011), synaptotagmin-4 (Zhang et al, 2011), PPAR-g (Lu et al, 2011;Ryan et al, 2011), NOS1 (Leshan et al, 2012), mitofusin (Dietrich et al, 2013;Schneeberger et al, 2013), P2Y6 (Steculorum et al, 2015), glucocorticoid (Quarta et al, 2017), Na v 1.7 (Branco et al, 2016), adenosine 1 receptor (Wu et al, 2017), and extended synaptotagmin-3 (Zhang et al, 2020), that play a significant role in maintaining energy balance or obesity development. It remains unclear, however, whether hypothalamic neuronal SOCE is crucial in either or both of these processes.…”

“…The procedures have been described previously (Zhang et al, 2008(Zhang et al, , 2020. To inject viruses into Arc nucleus, mice were anesthetized with Avertin (300 mg kg -1 ), and then were placed on an ultra-precise stereotaxic instrument (David Kopf, Tujunga, CA).…”