Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinase–activating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stress–dependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stress–dependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein E–deficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding. Conclusion : These data suggest that ER stress–dependent expression of hepatic VLDLR leads to hepatic steatosis by increasing lipoprotein delivery to the liver, which might be a novel mechanism explaining ER stress–induced hepatic steatosis.

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that regulates cellular redox potential. In this study, we demonstrate that macrophage G6PD plays an important role in the modulation of proinflammatory responses and oxidative stress. The G6PD levels in macrophages in the adipose tissue of obese animals were elevated, and G6PD mRNA levels positively correlated with those of proinflammatory genes. Lipopolysaccharide (LPS) and free fatty acids, which initiate proinflammatory signals, stimulated macrophage G6PD. Overexpression of macrophage G6PD potentiated the expression of proinflammatory and prooxidative genes responsible for the aggravation of insulin sensitivity in adipocytes. In contrast, when macrophage G6PD was inhibited or suppressed via chemical inhibitors or small interfering RNA (siRNA), respectively, basal and LPS-induced proinflammatory gene expression was attenuated. Furthermore, macrophage G6PD increased activation of the p38 mitogen-activated protein kinase (MAPK) and NF-B pathways, which may lead to a vicious cycle of oxidative stress and proinflammatory cascade. Together, these data suggest that an abnormal increase of G6PD in macrophages promotes oxidative stress and inflammatory responses in the adipose tissue of obese animals.

Lipid droplets (LDs) are key subcellular organelles for regulating lipid metabolism. Although several subcellular organelles participate in lipid metabolism, it remains elusive whether physical contacts between subcellular organelles and LDs might be involved in lipolysis upon nutritional deprivation. Here, we demonstrate that peroxisomes and peroxisomal protein PEX5 mediate fasting-induced lipolysis by stimulating adipose triglyceride lipase (ATGL) translocation onto LDs. During fasting, physical contacts between peroxisomes and LDs are increased by KIFC3-dependent movement of peroxisomes toward LDs, which facilitates spatial translocations of ATGL onto LDs. In addition, PEX5 could escort ATGL to contact points between peroxisomes and LDs in the presence of fasting cues. Moreover, in adipocytespecific PEX5-knockout mice, the recruitment of ATGL onto LDs was defective and fastinginduced lipolysis is attenuated. Collectively, these data suggest that physical contacts between peroxisomes and LDs are required for spatiotemporal translocation of ATGL, which is escorted by PEX5 upon fasting, to maintain energy homeostasis.

Obesity is characterized by excessive accumulation of lipid metabolites in adipose tissues as well as in nonadipose tissues, such as liver, muscle, and pancreas ( 1 ). Because obesity is considered as a major risk factor for most metabolic diseases, including hyperlipidemia, hypercholesterolemia, type 2 diabetes, hypertension, and cardiovascular disease ( 2-4 ), numerous investigations have been conducted to elucidate the key components in energy homeostasis, which is crucial to develop therapeutic agents for obesity and obesity-associated metabolic disorders.AMP-activated protein kinase (AMPK) is a master energy sensor that integrates nutrients, hormones, and stress signals to maintain whole-body energy homeostasis ( 5, 6 ). Under various stress conditions, AMPK is activated by allosteric stimulation in response to an increased AMP/ATP ratio or mitochondria activity change. AMPK activation also is induced by upstream stress kinases, such as liver kinase B1 (LKB1) or calcium/calmodulin-dependent protein kinase kinase (CaMKK) ( 7-10 ). Activated AMPK is involved in the regulation of diverse metabolic pathways.

SREBP1c is a key lipogenic transcription factor activated by insulin in the postprandial state. Although SREBP1c appears to be involved in suppression of hepatic gluconeogenesis, the molecular mechanism is not thoroughly understood. Here we show that CRY1 is activated by insulin-induced SREBP1c and decreases hepatic gluconeogenesis through FOXO1 degradation, at least, at specific circadian time points. SREBP1c−/− and CRY1−/− mice show higher blood glucose than wild-type (WT) mice in pyruvate tolerance tests, accompanied with enhanced expression of PEPCK and G6Pase genes. CRY1 promotes degradation of nuclear FOXO1 by promoting its binding to the ubiquitin E3 ligase MDM2. Although SREBP1c fails to upregulate CRY1 expression in db/db mice, overexpression of CRY1 attenuates hyperglycaemia through reduction of hepatic FOXO1 protein and gluconeogenic gene expression. These data suggest that insulin-activated SREBP1c downregulates gluconeogenesis through CRY1-mediated FOXO1 degradation and that dysregulation of hepatic SREBP1c-CRY1 signalling may contribute to hyperglycaemia in diabetic animals.