Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
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Bing Feng1, Jerney Harms1, Nirali Patel2
1Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA.
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. By using 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. Subsequently, we used an 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. Selective deletion of Cav3.2 in VgatARH neurons resulted in similar feeding inhibition and lean phenotype without changing energy expenditure. These 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 essential intrinsic modulator for food intake and energy homeostasis, which is a potential therapeutic target in the treatment of obesity.
Insights
Cav3.2 calcium channels in hypothalamic GABAergic neurons control food intake and body weight. Blocking Cav3.2 in these neurons reduces appetite and promotes a leaner phenotype, suggesting it as a therapeutic target for obesity.
Area of Science:
- Neuroscience
- Physiology
- Endocrinology
Background:
- Cav3.2 (T-type calcium channel) is crucial for neuronal excitability in the central nervous system.
- Its role in energy homeostasis, particularly concerning food intake and body weight regulation, remains largely unexplored.
- Hypothalamic GABAergic neurons are key regulators of appetite and metabolism.
Purpose of the Study:
- To investigate the role of Cav3.2 in hypothalamic GABAergic neurons in regulating food intake and body weight.
- To elucidate the underlying cellular and molecular mechanisms.
- To assess Cav3.2 as a potential therapeutic target for obesity.
Main Methods:
- Metabolic phenotyping of global Cav3.2 knockout (Cav3.2KO) mice and wild-type (WT) littermates.
- Selective deletion of Cav3.2 in GABAergic neurons of the arcuate nucleus of the hypothalamus (ARH) using CRISPR-Cas9 (Cav3.2KO-VgatARH).
- Electrophysiological patch-clamp recordings to assess neuronal excitability.
Main Results:
- Cav3.2KO mice exhibited reduced food intake, increased energy expenditure, and decreased body weight, fat mass, and lean mass.
- Selective deletion of Cav3.2 in VgatARH neurons mimicked the feeding inhibition and lean phenotype without altering energy expenditure.
- Naringenin treatment reduced VgatARH neuronal activity, food intake, and body weight, effects abolished in Cav3.2KO-VgatARH mice.
Conclusions:
- Cav3.2 within hypothalamic VgatARH neurons is an intrinsic regulator of food intake and energy balance.
- Targeting Cav3.2 in these neurons offers a potential strategy for managing obesity.
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