Adipocyte-specific NIK depletion enhances energy metabolism and glucose tolerance in mice

Nuclear factor κB (NF-κB)-inducing kinase (NIK) is a critical component of the noncanonical NF-κB pathway and an important regulator of immune response. NIK deficiency causes loss of lymph nodes, disruption of lymphoid organ structure and deficits in B-cell formation and immunoglobulin production. In this study, we generated adipocyte-specific NIK-knockout (Adipo-NIK-KO) mice to study the role of this protein in adipose tissue metabolism. We found that NIK depletion in mouse primary adipocytes potentiates thermogenic capacity without altering the differentiation of these cells. Loss of NIK in adipocytes stimulated Fibroblast growth factor 21 (FGF21)-induced expression of thermogenic genes, including Uncoupling protein 1 (UCP1) and mitochondrial uncoupled respiration. In fact, enhanced browning of subcutaneous fat depots was detected in Adipo-NIK-KO mice, which also had elevated energy expenditure. These mice exhibited improved glucose tolerance and insulin sensitivity and reduced hepatic lipid deposition upon diet-induced obesity. Similarly, inhibition of NIK by a specific small molecule enhanced metabolic rate and glucose homeostasis in obese mice. Therefore, NIK inhibition holds therapeutic potential for reversing glucose intolerance and insulin resistance associated with obesity.