Lipocalin2 regulates the p38MAPK‐PGC1α‐UCP1 pathway to activate the thermogenic program in subcutaneous white adipocytes via a non‐adrenergic mechanism (133.5)

Abstract

Thermogenic activity in adipocytes is negatively correlated with obesity. Adrenergic activation of p38 mitogen‐activated protein kinase (p38MAPK) mediated thermogenesis is well established. Recently, non‐adrenergic regulation of thermogenesis has gained interest. Lipocalin 2 (Lcn2) is a novel adipokine whose deficiency induces cold intolerance in mice. Herein, we explored the thermogenic effect of Lcn2 and its underlying mechanism in subcutaneous white adipocytes. Inguinal stromal‐vascular cells were collected from wild‐type (WT) and Lcn2‐/‐ mice and differentiated to adipocytes. Lcn2‐/‐ mice had a downregulation of uncoupling protein 1 (UCP1) expression in inguinal adipose tissue (iWAT) compared to WT mice on a high fat diet. Lcn2‐/‐ inguinal adipocytes showed significantly lower UCP1 and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) expression as well as p38MAPK phosphorylation when compared to WT cells. However, norepinephrine‐induced UCP1 and PGC1α transcription, lipolysis and p38MAPK phosphorylation remained unchanged in Lcn2‐/‐ adipocytes. Additionally, Lcn2 recombinant markedly upregulates UCP1 and PGC1α transcription, and increases p38MAPK phosphorylation in Lcn2‐/‐ inguinal adipocytes. This effect is more pronounced under insulin‐stimulated conditions, suggesting Lcn2 synergizes with insulin to activate thermogenic programming. Moreover, a p38MAPK inhibitor attenuated Lcn2‐induced UCP1 expression. In conclusion, Lcn2 has a significant role in promoting iWAT thermogenesis by upregulating the p38MAPK‐PGC1α‐UCP1 pathway via a non‐adrenergic mechanism.Grant Funding Source: Supported by NIDDK