NF-κB-Inducing Kinase Maintains Mitochondrial Efficiency and Systemic Metabolic Homeostasis

Abstract

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 NF-κB-inducing kinase (NIK), a critical regulator of immunity and inflammation has local and systemic effects on metabolic processes. We demonstrate that NIK has NF-κB-independent and -dependent roles on adipose development and function. Independently of noncanonical NF-κB, 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-κB 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.

NF-κB-Inducing Kinase (NIK) Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells

“…We have recently observed that NIK KO mice exhibit altered systemic metabolism characterized by an increase in aerobic glycolysis and impaired respiration (32), which is similar to patients with primary mitochondrial diseases (MD) caused by mutations in OXPHOS genes. Patients with MD often experience recurrent infections and display adaptive immunodeficiency (39,40), paralleling those with NIK loss-of-function PID.…”

“…How loss of NIK function alters innate immune cell development and function in patients with PID is unclear, and the impact of NIK dysregulation on immunometabolic homeostasis in PID has not been previously considered. We have recently observed that NIK KO mice exhibit altered systemic metabolism characterized by an increase in aerobic glycolysis and impaired respiration (32), which is similar to patients with primary mitochondrial diseases (MD) caused by mutations in OXPHOS genes. Patients with MD often experience recurrent infections and display adaptive immunodeficiency (39, 40), paralleling those with NIK loss-of-function PID.…”

“…Because little is known about the role of NIK within macrophages, we investigated the relationship between the accumulated eosinophils and their effect on macrophage polarization in the visceral white adipose tissue (WAT) deposits, which are known to have low eosinophil numbers and high levels of macrophages, along with the small intestine, which has high eosinophil numbers and low levels of macrophages (28,30,31). It was previously reported that NIK KO mice have a decrease in body weight compared to WT controls, which also correlates with a decrease in fat mass and smaller adipocytes (32). We found NIK KO mice had a significant accumulation of lineage positive immune cells within the WAT compared to WT littermates and further analysis of the immune populations revealed a significant increase in macrophages and a similar trend in eosinophils (Figure 3G-J).…”

The Therapeutic Potential of Targeting NIK in B Cell Malignancies

“…B022 has also been used to treat mice in the context of alcoholic liver disease, where it alleviated alcoholic steatosis, yet toxicities remain unclear ( 82 ). Finally, in vitro B022 treatment of mouse stem cells prevented adipogenesis and inhibited non-canonical NF-κB signaling ( 86 ). Although these cells do not show nuclear canonical NF-κB, B022 treatment did reduce cytoplasmic RelA phosphorylation levels.…”