DYSREGULATION OF LIPOLYSIS AND LIPID METABOLISM IN VISCERAL AND SUBCUTANEOUS ADIPOCYTES BY HIGH‐FAT DIET

This study investigated the molecular mechanisms by which high‐fat diet (HFD) dysregulates lipolysis and lipid metabolism in mouse epididymal (visceral, VC) and inguinal (subcutaneous, SC) adipocytes. HFD feeding increased ATGL content and CGI‐58 expression, whereas HSL phosphorylation and perilipin content were reduced. This was accompanied by increased basal but blunted epinephrine‐stimulated lipolysis and increased DAG content in VC and SC adipocytes. In HFD VC adipocytes, activation of adenylyl cyclases by forskolin increased HSL phoshorylation and matched the lipolytic response of control VC cells. However, in HFD SC adipocytes, forskolin induced lipolysis without detectable HSL phosphorylation. This suggests activation of an alternative lipase in response to the HFD‐induced suppression of HSL phosphorylation/activation in VC and SC adipocytes. HFD also powerfully inhibited basal, epinephrine‐, and forskolin‐induced AMPK activation as well as the expression of PGC‐1α and PPARα, citrate synthase activity, and palmitate oxidation in both fat depots. In summary, defective adrenergic receptor signaling combined with up‐regulation of ATGL, and suppression of HSL and AMPK signaling mediate HFD‐induced dysregulation of lipolysis and lipid metabolism in VC and SC adipocytes.