Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice

Salt-Inducible Kinase 3 (SIK3) has emerged as a key regulator of peripheral metabolism, however its cellular and molecular function in regulating body weight and energy metabolism, particularly in hypothalamic neurons, remains unclear and largely unexplored. Here, we demonstrate that SIK3 expression is elevated in the hypothalamus of obese mice. Inactivation of SIK3 specifically in orexigenic NPY neurons reduces food intake, increases energy expenditure, and enhances white adipose tissue browning, resulting in resistance to high-fat diet-induced obesity in mice. Pharmacological inhibition of SIK3 with the inhibitor GLPG3970 in diet-induced obese mice led to significant reductions in body weight and adiposity, primarily due to decreased energy intake, with notable improvements in metabolic health. These effects are linked to enhanced central leptin and insulin signaling, and the dephosphorylation and nuclear translocation of key transcriptional metabolic regulators, CRTC1 and HDAC5. These findings reveal a previously unidentified SIK3-mediated pathway that promotes positive energy balance and suggests SIK3 inhibition may offer therapeutic potential for treating obesity and metabolic disorders.