SUMMARY Reduced expression of the Indy (= I am Not Dead, Yet) gene in D. melanogaster and C. elegans prolongs life span, and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout-mouse model of the mammalian Indy (mIndy) homologue, SLC13A5. Deletion of mIndy in mice (mINDY−/− mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1α, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect mINDY−/− mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.

OBJECTIVEMacrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation.RESEARCH DESIGN AND METHODSWe used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects.RESULTSWe found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration.CONCLUSIONSReduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.

Hepatic gluconeogenesis is a major contributing factor to hyperglycemia in the fasting and postprandial states in type 2 diabetes mellitus (T2DM). Because Sirtuin 1 (SirT1) induces hepatic gluconeogenesis during fasting through the induction of phosphoenolpyruvate carboxylase kinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducing SirT1, by using an antisense oligonucleotide (ASO), would decrease fasting hyperglycemia in a rat model of T2DM. SirT1 ASO lowered both fasting glucose concentration and hepatic glucose production in the T2DM rat model. Whole body insulin sensitivity was also increased in the SirT1 ASO treated rats as reflected by a 25% increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemiceuglycemic clamp and could entirely be attributed to increased suppression of hepatic glucose production by insulin. The reduction in basal and clamped rates of glucose production could in turn be attributed to decreased expression of PEPCK, FBPase, and G6Pase due to increased acetylation of signal transducer and activator of transcription 3 (STAT3), forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣), known substrates of SirT1. In addition to the effects on glucose metabolism, SirT1 ASO decreased plasma total cholesterol, which was attributed to increased cholesterol uptake and export from the liver. These results indicate that inhibition of hepatic SirT1 may be an attractive approach for treatment of T2DM. gluconeogenesis ͉ glucose 6 phosphatase ͉ phosphoenolpyruvate carboxykinase ͉ type 2 diabetes mellitus ͉ hepatic insulin resistance T ype 2 diabetes mellitus (T2DM) is associated with an increased rate of hepatic glucose production that contributes to fasting hyperglycemia (1-3). Specifically, increased endogenous glucose production can be accounted for by increased rates of hepatic gluconeogenesis (4). Inhibition of hepatic gluconeogenesis has been shown to improve fasting plasma glucose levels and decrease endogenous glucose production in T2DM patients (5). Furthermore, inhibition of transcriptional gluconeogenic activators, such as forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣), in turn improved hepatic insulin resistance in rodent models of diabetes (6, 7). Therefore inhibitors of gluconeogenesis are potentially excellent targets for treatment of poorly controlled T2DM.Sirtuin1 (SirT1) is a NAD ϩ -dependent deacetylase activated in response to fasting and caloric restriction (8). In the ␤-cells of the pancreas, SirT1 has been shown to increase insulin secretion through repression of uncoupling protein 2 (UCP2) (9). In adipose tissue, SirT1 has been shown to inhibit adipogenesis and decrease lipolysis through inhibition of peroxisome proliferator-activated receptor-␥ (PPAR␥) (10). In liver tissue, SirT1 activates gluconeogenesis transcription through deacetylation of PGC-1␣, FOXO1, and signa...

Summary N-acylphosphatidylethanolamines (NAPEs) are a relatively abundant group of plasma lipids of unknown physiological significance. Here we show that NAPEs are secreted into circulation from the small intestine in response to ingested fat, and that systemic administration of the most abundant circulating NAPE, at physiologic doses, decreases food intake in rats without causing conditioned taste aversion. Furthermore, 14C-radiolabeled NAPE enters the brain and is particularly concentrated in the hypothalamus, and intracerebroventricular infusions of nanomolar amounts of NAPE reduce food intake, collectively suggesting that its effects may be mediated through direct interactions with the central nervous system. Finally, chronic NAPE infusion results in a reduction of both food intake and body weight, suggesting that NAPE and long acting NAPE analogues may be novel therapeutic targets for the treatment of obesity.