NF-κB-inducing kinase maintains mitochondrial efficiency and systemic metabolic homeostasis

NF-κB-inducing kinase (NIK) is an essential upstream inducer of noncanonical NF-κB signaling and a critical regulator of immunity and inflammation. Our recent work has demonstrated that NIK regulates mitochondrial respiration and adaptive metabolic responses in cancer and innate immune cells. However, it is not clear whether NIK also has roles in regulating systemic metabolism. In this study, we demonstrate that NIK has local and systemic effects on developmental and metabolic processes. Our findings show that NIK-deficient mice exhibit reduced adiposity, as well as elevated energy expenditure both basally, and under the stress of a high-fat diet. Moreover, we identify NF-κB-independent and -dependent functions for NIK in white adipose tissue metabolism and development. Specifically, we found that in an NF-κB-independent manner NIK is required for maintaining mitochondrial fitness, as NIK-deficient adipocytes have impaired mitochondrial membrane potential and spare respiratory capacity. In addition to mitochondrial exhaustion, NIK-deficient adipocytes and ex vivo adipose tissue exhibit a compensatory upregulation of glycolysis to meet bioenergetic demands. Finally, while NIK regulation of mitochondrial metabolism in preadipocytes is NF-κB-independent, we demonstrate that NIK has a complementary role in adipocyte differentiation that requires activation of RelB and the noncanonical NF-κB pathway. Collectively, these data demonstrate that NIK has critical roles in local and systemic development and metabolism. Our findings establish NIK as an important regulator of organelle, cell, and systemic metabolic homeostasis, suggesting that metabolic dysfunction may be an important and unappreciated component of immune disorders and inflammatory diseases arising from NIK deficiency. •NIK promotes mitochondrial efficiency by enhancing mitochondrial spare respiratory capacity and reducing proton leak.•NIK-deficient preadipocytes and ex vivo adipose tissue exhibit inefficient mitochondrial metabolism and increased glycolysis.•NIK knockout mice exhibit elevated metabolism with increased glucose utilization, glycolysis, and energy expenditure.•NIK knockout mice have reduced adiposity that persists under chronic over-nutrition with a high-fat diet.•NIK promotes adiposity through NF-κB-independent control of metabolism, and NF-κB-dependent adipocyte differentiation.