Obesity results from chronic energy surplus and excess lipid storage in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) efficiently burns lipids through adaptive thermogenesis. Studying mouse models, we show that cyclooxygenase (COX)-2, a rate-limiting enzyme in prostaglandin (PG) synthesis, is a downstream effector of beta-adrenergic signaling in WAT and is required for the induction of BAT in WAT depots. PG shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX-2 in WAT induced de novo BAT recruitment in WAT, increased systemic energy expenditure, and protected mice against high-fat diet-induced obesity. Thus, COX-2 appears integral to de novo BAT recruitment, which suggests that the PG pathway regulates systemic energy homeostasis.

OBJECTIVE-In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. In contrast, aberrantly high levels of triglycerides in the blood ("hypertriglyceridemia") represent a hallmark of the metabolic syndrome and type 2 diabetes. As hypertriglyceridemia has been identified as an important risk factor for cardiovascular complications, in this study we aimed to identify molecular mechanisms in aberrant triglyceride elevation under these conditions. RESEARCH DESIGN AND METHODS-To determine the importance of hepatic lipid handling for systemic dyslipidemia, we profiled the expression patterns of various hepatic lipid transporters and receptors under healthy and type 2 diabetic conditions. A differentially expressed lipoprotein receptor was functionally characterized by generating acute, liver-specific loss-and gain-of-function animal models. RESULTS-Weshow that the hepatic expression of lipid transporter lipolysis-stimulated lipoprotein receptor (LSR) is specifically impaired in mouse models of obesity and type 2 diabetes and can be restored by leptin replacement. Experimental imitation of this pathophysiological situation by liver-specific knockdown of LSR promotes hypertriglyceridemia and elevated apolipoprotein (Apo)B and E serum levels in lean wild-type and ApoE knockout mice. In contrast, genetic restoration of LSR expression in obese animals to wild-type levels improves serum triglyceride levels and serum profiles in these mice. CONCLUSIONS-The dysregulation of hepatic LSR under obese and diabetic conditions may provide a molecular rationale for systemic dyslipidemia in type 2 diabetes and the metabolic syndrome and represent a novel target for alternative treatment strategies in these patients. Diabetes 58:1040-1049, 2009 A ccording to recent estimates, obesity-related type 2 diabetes will be diagnosed in 200 -300 million people worldwide in 2010 (1). As part of the so-called metabolic syndrome, chronic hyperglycemia and dyslipidemia represent major causes for vascular complications in type 2 diabetic patients and result from defects in endocrine control systems that under normal conditions strictly balance glucose and lipid homeostasis within narrow limits (2).Dyslipidemia, as associated with diabetic metabolism and the metabolic syndrome, is characterized by a socalled proatherogenic blood lipid profile, comprising low levels of HDLs, increased LDLs, and strongly increased levels of serum triglycerides associated with VLDLs. Indeed, hepatic VLDL release is increased in diabetes and is thought to drive other aspects of the dyslipidemia associated with this disorder (3). In fact, hypertriglyceridemia is considered to represent an important risk factor for atherosclerosis and subsequent cardiovascular complications in type 2 diabetic patients (4).The regulation of plasma triglyceride levels is conferred through a complex interplay between different tissues and cell types (5). Dietary triglycerides within chylomicrons are hydrolyzed by adip...