TNF‐α Upregulates IKKε Expression via the Lin28B/let‐7a Pathway to Induce Catecholamine Resistance in Adipocytes

Abstract

Objective Overexpression of inhibitor of nuclear factor kappa‐B kinase subunit epsilon (IKKε) contributes to blunted catecholamine‐induced lipolysis. Tumor necrosis factor α (TNF‐α) upregulates adipose IKKε expression to inhibit stimulated lipolysis, which can be reversed by IKKε inhibitors. This study investigated adipose IKKε expression in children with and without obesity and potential involvement of the Lin28B/let‐7a axis in posttranscriptional regulation of TNF‐α‐stimulated IKKε in adipocytes. Methods Adipose IKKε was detected in children both with and without obesity. The effects of TNF‐α on IKKε expression of adipocytes were investigated. Inhibitor and mimics of microRNA let‐7a or short interfering RNA of protein lin‐28 homolog B (Lin28B) were used to determine the effect of the Lin28B/let‐7a axis on TNF‐α‐mediated IKKε upregulation. Reporter assays were performed to confirm that let‐7a targets the IKKε gene. Results Adipose IKKε expression in children with obesity was upregulated to a greater extent than that in children without obesity and was positively correlated with BMI. TNF‐α increased IKKε expression through activation of Lin28B/let‐7a and then inhibited isoproterenol‐stimulated lipolysis in adipocytes. Blocking the Lin28B /let‐7a axis rescued inhibition of isoproterenol‐stimulated lipolysis produced by TNF‐α by inhibiting IKKε expression. Reporter assays confirmed that IKKε is a target of let‐7a. Conclusions Adipose IKKε expression in children with obesity is substantially elevated and positively correlated with BMI. TNF‐α induces catecholamine resistance via activation of the Lin28B/let‐7a/IKKε pathway.

FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition

“…This was accompanied by increased browning or beiging of subcutaneous white adipose tissue, along with the increased expression of thermogenic genes such as Ucp1 and others. This finding was consistent with increases in catecholamine sensitivity observed with inhibition or knockout of IKKe in adipocytes (30,31), and suggests that increased cAMP signaling in adipocytes is responsible for elevated energy expenditure. Of note, while UCP1 expression correlates with adipose tissue beiging and energy expenditure, mitochondrial defects in UCP1 KO mice (66) preclude the exclusion of UCP1-independent changes in mitochondrial bioenergetics that may also contribute to energy expenditure.…”

“…A primary target of amlexanox in rodents is the subcutaneous adipose tissue, where it increases energy expenditure partly by enhancing catecholamine sensitivity via inhibition of IKKe (30) and browning of adipocytes (23). Increased IKKe expression has also been linked with catecholamine resistance in adipocytes from obese children (31). The increase in catecholamine sensitivity with amlexanox treatment in mice resulted in a transient increase in IL-6 synthesis and secretion from adipocytes and preadipocytes, which was responsible for acute lowering of blood sugar via reduced hepatic glucose output (32).…”

Multi-Level Regulatory Interactions between NF-κB and the Pluripotency Factor Lin28

“…The tissue and cellular expression profiles for Lin28a and Lin28b in mammals remain somewhat enigmatic, with low or undetectable levels reported in adults for most regions, with the exception of the testes, in atlas sources for mouse and human (e.g., www.proteinatlas.org). This stands in possible discrepancy to accumulating reports of Lin28a and Lin28b presence and function in adult organisms or differentiated cells and tissues [34][35][36][37][38][39][40][41][42][43][44][45][46][47], despite clear downregulation in levels from early development. Ineffective detection is not unfamiliar amongst low abundance proteins and transcripts which may not be readily quantified or documented in databases and could be contributed to by a failure to capture signal-dependent upregulation.…”

Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina

“…However, our data cannot rule out other potential causes. For example, in vitro incubation of adipocytes with TNF-α reduces lipolysis in response to β-adrenergic agonists [46], suggesting that inflammation could aggravate catecholamine resistance. Adipose tissue releases NEFA during lipolysis and the only plasma metabolite that differed between SST-DTA mice and controls were NEFA, which showed dynamic differences: an early increase followed by a late decline.…”