Targeting Gβγ subunits in hypothalamic AgRP neurons to treat obesity.

G protein-coupled receptors (GPCRs) in the central nervous system, particularly in the hypothalamus, are promising therapeutic targets for the treatment of obesity and related metabolic disorders. However, the development of anti-obesity drugs targeting GPCRs in hypothalamus has been significantly constrained by their propensity to induce a range of adverse effects. An alternative strategy is to directly target the G protein subunits downstream of GPCRs, potentially biasing GPCR signaling away from harmful pathways while preserving those essential for normal cellular functions. The G protein βγ (Gβγ) subunits have emerged as a potential therapeutic target, but its role in obesity is largely unknown. In this study, we found that gallein, a Gβγ inhibitor, can ameliorate diet-induced obesity (DIO) and related metabolic dysfunction by suppressing appetite. Given the critical role of hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons in maintaining whole-body energy balance, we further demonstrated that gallein suppressed appetite by inhibiting AgRP neuronal activity. More importantly, specific inhibition of Gβγ subunits in AgRP neurons can inhibit the activation of AgRP neurons, thereby reducing food intake and ameliorating DIO and related metabolic dysfunction. Conversely, overexpression of Gβγ in AgRP neurons promoted hyperphagia and obesity. Mechanistically, we discovered that Gβγ subunits increase AMPK activity to promote mitochondrial fatty acid oxidation and ATP production, ultimately increasing the activity of AgRP neurons and related peptide expression. In conclusion, our study demonstrates that Gβγ subunits regulate feeding and metabolism through multiple bioenergetic processes in AgRP neurons. Gallein, the small-molecule inhibitor of Gβγ subunits emerges as a promising therapeutic candidate for obesity and its associated comorbidities.