Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

Abstract

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 (Vgat ARH ) neurons. These male mutants (Cav3.2KO-Vgat ARH ) were used to determine whether Cav3.2 expressed by Vgat ARH 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 Vgat ARH 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 Vgat ARH 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 Vgat ARH neurons and reduced food intake and body weight. These naringenin-induced inhibitions were fully blocked in Cav3.2KO-Vgat ARH mice. Conclusion Our results identified Cav3.2 expressed by Vgat ARH neurons as an essential intrinsic modulator for food intake and energy homeostasis, which is a potential therapeutic target in the treatment of obesity.

Could Naringenin Participate as a Regulator of Obesity and Satiety?

“…The same study also proposes that the effect of NAR on CCK is mediated by activating the TRPA1 channel, which allows the entry of extracellular calcium into the cell, since antagonists of this channel countered the effect of NAR on CCK. This is in agreement with the findings of Feng et al [ 102 ], who reported the blockade of ion channels in ARC neurons after NAR administration. Thus, NAR appears to exert some of its effects by modulating ion channel activity and intracellular calcium signaling ( Figure 3 ).…”

“…Most in vivo and in vitro studies describe a dose-dependent effect of NAR [ 19 , 42 , 87 ], still, its use has been studied in vivo at low doses (25 mg/kg body weight) [ 19 ] in a short period of time (2 days, intraperitoneal) [ 102 ] with positive results (see Table 1 ), which may support its use as a dietary supplement [ 65 ]. It is also important to consider that the documented effects regarding NAR are mainly preventive, protective and related to an improvement, but are not curative.…”

Cav3.2 deletion attenuates nonalcoholic fatty liver disease in mice

“…As a main member of the T-type calcium channel, Cav3.2 channel has been reported to widely present in tissues throughout the body, including heart, brain, liver, lung, kidney and skin [12,29] . Numerous studies suggested that Cav3.2 channel play a crucial part in the development of various diseases, including myocardial infarction [13] , hypertension [14] , obesity [15] and diabetic neuropathy [16] . In addition, Cav3.2 inhibitors mibefradil and NNC 55-0396 were proven to improve hyperglycemia and hyperlipidemia in db/db mice [30] .…”

“…Cav3.2 channel is an important member of T-type calcium channel and involved in many cellular processes with different cell activities by regulating calcium in ux, including proliferation, migration, differentiation and apoptosis [11,12] . Numerous studies suggested that Cav3.2 channel play a crucial part in the development of various diseases, including myocardial infarction [13] , hypertension [14] , obesity [15] and diabetic neuropathy [16] . However, little is known on the function of Cav3.2 channel in the progression of NAFLD.…”

Emulsão A/O/A para o carreamento de cálcio e vitamina D e seu impacto na qualidade sensorial de patê de soja

“…Sua principal fonte é o leite, seguido de vegetais e frutas. Baixos níveis séricos de cálcio no organismo têm sido associados a doenças como: osteoporose (Bae et al, 2022;Shen et al, 2021;Taylor & Elbadawy, 2006), osteomalácia (Taylor & Elbadawy, 2006), hipertensão (Potje et al, 2021), obesidade (Feng et al, 2021;Hastert et al, 2021), raquitismo (Mays & Brickley, 2022), enfraquecimento dos dentes e redução da capacidade de coagulação do sangue .…”