Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
| Autor: | Hui Ye, Ann A. Coulter, Heike Münzberg, Christopher D. Morrison, Pei Luo, Patel Nirali, Bing Feng, Hans-Rudolf Berthoud, Yanlin He, Pingwen Xu, Candida J. Rebello, Sangho Yu, Jerney Harms, Jia Fan, Valeria Torres Irizarry, Jacob Vidrine, Frank L. Greenway |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Central nervous system Hypothalamus Biology Energy homeostasis Calcium Channels T-Type Mice Arcuate nucleus Naringenin Internal medicine medicine Animals Obesity GABAergic Neurons Molecular Biology Mice Knockout Calcium channel Feeding T-type calcium channel Wild type GABA neurons Cell Biology RC31-1245 Mice Inbred C57BL Cav3.2 medicine.anatomical_structure Endocrinology GABAergic Original Article |
| Zdroj: | Molecular Metabolism, Vol 54, Iss, Pp 101391-(2021) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Cav3.2, a T-type low voltage-activated calcium channel widely expressed throughout the central nervous system, plays a vital role in neuronal excitability and various physiological functions. However, the effects of Cav3.2 on energy homeostasis remain unclear. Here we examined the role of Cav3.2 expressed by hypothalamic GABAergic neurons in the regulation of food intake and body weight in mice and explored the underlying mechanisms. Methods Male congenital Cana1h (the gene coding for Cav3.2) global knockout (Cav3.2KO) mice and their wild type (WT) littermates were first used for metabolic phenotyping studies. Subsequently, with the help of the CRISPR-Cas9 technique, Cav3.2 was selectively deleted from GABAergic neurons in the arcuate nucleus of the hypothalamus (ARH) by specifically overexpressing Cas9 protein and Cav3.2-targeting sgRNAs in ARH Vgat (VgatARH) neurons. These male mutants (Cav3.2KO-VgatARH) were used to determine whether Cav3.2 expressed by VgatARH neurons is required for the proper regulation of energy balance. Finally, we employed electrophysiological patch-clamp recording in ex vivo brain slices to explore the impact of Cav3.2KO on the cellular excitability of VgatARH neurons. Results Male Cav3.2KO mice had significantly lower food intake than their WT littermate controls when fed with either a normal chow diet (NCD) or a high-fat diet (HFD). This hypophagia phenotype was associated with increased energy expenditure and decreased fat mass, lean mass, and total body weight. Additionally, selective deletion of Cav3.2 in VgatARH neurons resulted in similar feeding inhibition and lean phenotype without changing energy expenditure. This data provides an intrinsic mechanism to support the previous finding on ARH non-AgRP GABA neurons in regulating diet-induced obesity. Lastly, we found that naringenin extract, a predominant flavanone found in various fruits and herbs and known to act on Cav3.2, decreased the firing activity of VgatARH neurons and reduced food intake and body weight. These naringenin-induced inhibitions were fully blocked in Cav3.2KO-VgatARH mice. Conclusion Our results identified Cav3.2 expressed by VgatARH neurons as an important intrinsic modulator for food intake and energy homeostasis, which is a potential therapeutic target in the treatment of obesity. |
| Databáze: | OpenAIRE |
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