NF-?B-inducing kinase (NIK), the essential upstream kinase which regulates activation of the noncanonical NF-?B pathway, has important roles in regulating immunity and inflammation. In addition, NIK is vital for maintaining cellular health through its control of fundamental cellular processes, including differentiation, growth, and cell survival. As such aberrant expression or regulation of NIK is associated with several disease states. For example, loss of NIK leads to immune defects, while the overexpression of NIK is observed in inflammatory diseases, metabolic disorders, and the development and progression of cancer. Obesity is a predominant risk factor for metabolic syndrome, which refers to a cluster of disorders that include diabetes, cardiovascular disease and fatty liver disease. Obesity and overnutrition are associated with aberrant immune and inflammatory responses resulting in increased local fat deposition, insulin resistance and systemic metabolic dysregulation. Here we show NIK has local and systemic effects on metabolic processes. We demonstrate that NIK has NF-?B-independent and -dependent roles on adipose development and function. Independently of noncanonical NF-?B, NIK deficiency regulates mitochondrial spare respiratory capacity (SRC) and proton leak but establishes higher basal oxygen consumption and glycolytic capacity in preadipocytes and ex vivo adipose tissue. In addition, we demonstrate NIK promotes adipogenesis through its role in activation of the noncanonical NF-?B pathway. Strikingly, when challenged with a high fat diet, NIK deficient mice are protected against diet-induced obesity and insulin insensitivity. Overall, mice lacking NIK exhibit decreased overall fat mass and increased energy expenditure. Our results establish that, through its influences on adipose development, metabolic homeostasis and rewiring, NIK is a driver of pathologies associated with metabolic dysfunction. Furthermore, as aberrant expression or regulation of NIK is associated with several disease states including cancer progression it is of interest to investigate effective ways of targeting chemotherapeutics to tumor cells including that of NIK or other kinase inhibitors. A novel method of specifically targeting chemotherapeutics to tumor cells involves the conjugation of heptamethine cyanine dyes. We show that use of these dyes improves chemotherapeutic efficacy in passing the blood brain barrier and treating glioblastoma.
