Dataset Information

Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons.

ABSTRACT: Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRP^ARH neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of asprosin/Ptprd on AgRP^ARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRP^ARH neurons, respectively. AgRP^ARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRP^ARH neurons) blocked asprosin-induced AgRP^ARH activation and overeating. Furthermore, pharmacological blockade, genetic knockdown, or knockout of Ptprd abolished asprosin's effects on the SK current and AgRP^ARH neuronal activity. Therefore, our results demonstrated an essential asprosin-Ptprd-SK3 mechanism in asprosin-induced AgRP^ARH activation and hyperphagia, which is a potential therapeutic target for the treatment of obesity.

SUBMITTER: Feng B

PROVIDER: S-EPMC9946352 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons.

Feng Bing B Liu Hesong H Mishra Ila I Duerrschmid Clemens C Gao Peiyu P Xu Pingwen P Wang Chunmei C He Yanlin Y

Science advances 20230222 8

Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRP<sup>ARH</sup> neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of aspro ...[more]

PMID: 36812308

Similar Datasets

Project description:BackgroundFatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance.MethodsTo obtain Cpt1aKO mice and their control littermates, Cpt1a(flox/flox) mice were crossed with tamoxifen-inducible AgRPCreERT2 mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting-refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin-angiotensin-aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag-Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex.ResultsChanges in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations.ConclusionsOur results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.

Dataset Information

Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons.

Publications

Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets