Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signaling, with FoxO1 presiding over glucose production and Srebp–1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.

Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of type 2 diabetes. A rat model of maternal protein restriction has been used to investigate the mechanistic basis of this relationship. This model causes insulin resistance and diabetes in adult male offspring. The aim of the present study was to determine the effect of early growth restriction on muscle insulin action in late adult life. Rats were fed either a 20% or an isocaloric 8% protein diet during pregnancy and lactation. Offspring were weaned onto a 20% protein diet and studied at 15 months of age. Soleus muscle from growth restricted offspring (LP) (of dams fed 8% protein diet) had similar basal glucose uptakes compared with the control group (mothers fed 20% protein diet). Insulin stimulated glucose uptake into control muscle but had no effect on LP muscle. This impaired insulin action was not related to changes in expression of either the insulin receptor or glucose transporter 4 (GLUT 4). However, LP muscle expressed significantly less (P<0·001) of the zeta isoform of protein kinase C (PKC ) compared with controls. This PKC isoform has been shown to be positively involved in GLUT 4-mediated glucose transport. Expression levels of other isoforms ( I, II, ε, ) of PKC were similar in both groups. These results suggest that maternal protein restriction leads to muscle insulin resistance. Reduced expression of PKC may contribute to the mechanistic basis of this resistance.

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1 −/− mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1 −/− mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD + , and is associated with obesity resistance. Consistent with this, NAD + levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences.

The elucidation of extra-nuclear lysine acetylation has been of growing interest, as the co-substrate for acetylation, acetyl CoA, is at a key metabolic intersection. Our hypothesis was that mitochondrial and cytoplasmic protein acetylation may be part of a fasted/re-fed feedback control system for the regulation of the metabolic network in fuel switching, where acetyl CoA would be provided by fatty acid oxidation, or glycolysis, respectively. To test this we characterized the mitochondrial and cytoplasmic acetylome in various organs that have a high metabolic rate relative to their mass, and/or switch fuels, under fasted and re-fed conditions (brain, kidney, liver, skeletal muscle, heart muscle, white and brown adipose tissues). Using immunoprecipitation, coupled with LC-MSMS label free quantification, we show there is a dramatic variation in global quantitative profiles of acetylated proteins from different organs. In total, 733 acetylated peptides from 337 proteins were identified and quantified, out of which 31 acetylated peptides from the metabolic proteins that may play organ-specific roles were analyzed in detail. Results suggest that fasted/re-fed acetylation changes coordinated by organ-specific (de-)acetylases in insulin-sensitive versus insensitive organs may underlie fuel use and switching. Characterization of the tissue-specific acetylome should increase understanding of metabolic conditions wherein normal fuel switching is disrupted, such as in Type II diabetes.

Objective Data from animal models show that in utero exposure to a maternal high fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering risk of adult disease. Because mice heterozygous for GLUT4 (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to a high fat diet in utero, we sought to analyze the genome-wide epigenetic changes which occur in the fetal liver in susceptible offspring. Study Design WT and Glut4+/− (G4+/−) offspring of WT mothers exposed either to a control or a HF diet in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5 week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP on chip) was utilized to detect genome-wide changes of histone modifications with HFD exposure. Results We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4+/− fetal and 5 week offspring. Pathway analysis of our ChIP on chip data reveal differential H3K14ac and H3K9me3 enrichment along pathways which regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra and Rora. Conclusion We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4+/− offspring, some which persist up to 5 weeks of age.