Project description:Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondrial-associated ER membrane. Recently, great advances have been made in the understanding of inter-organelle communication between the ER and mitochondria. To clarify the role of mitochondrial dynamics in this communication, we generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (Drp1) in the liver (Drp1LiKO). While intake of a high-fat diet (HFD) resulted in histological changes characterized by hepatic steatosis, inflammation, apoptosis, necrosis and fibrosis, reminiscent of nonalcoholic steatohepatitis, Drp1LiKO mice showed decreased fat mass and were protected from HFD-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of fibroblast growth factor 21 (Fgf21) through induction of activating transcription factor 4 and X-box binding protein 1, master regulators of the integrated stress response.
Project description:Obesity-induced inflammation metabolic dysfunction, but the mechanisms remain elusive. Here we showed that the innate immune factor IRF3 is a direct transcriptional regulator of glucose homeostasis through induction of endogenous FAHFA hydrolase Aig1 in adipocytes. Adipocyte-specific knockout IRF3 protects mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.
Project description:Exercise benefits M2 macrophage polarization, energy homeostasis and protects against obesity partially through exercise-induced circulating factors. Here, by unbiased quantitative proteomics on serum samples from sedentary and exercised mice, we identify parvalbumin as a circulating factor suppressed by exercise. Parvalbumin functions as a non-competitive CSF1R antagonist to inhibit M2 macrophage activation and energy expenditure in adipose tissue. More importantly, serum concentrations of parvalbumin positively correlate with obesity in mouse and human, while treating mice with a recombinant parvalbumin blocker prevents its interaction with CSF1R and promotes M2 macrophage polarization and ameliorates diet-induced obesity. Thus, although further studies are required to assess the significance of parvalbumin in mediating the effects of exercise, our results implicate parvalbumin as a potential therapeutic strategy against obesity.
Project description:Global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle but not adipose tissue or liver led to protection from high-fat diet induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable shaped filaments, increased mitochondrial respiration, but attenuated exercise performance. Mice used for microarray analyses were all male, and chronically exposed to HFD for at least 8 weeks.
Project description:The induction of beige/brite adipose cells in white adipose tissue (WAT) is associated with protection against high fat diet-induced obesity and insulin resistance in animals. The helix-loop-helix transcription factor Early B-Cell Factor-2 (EBF2) regulates brown adipose tissue development. We examined the role of EBF2 in beige fat cell biogenesis by comparing transcriptome in wildtype and EBF2-overexpressing mice in the adipose tissue. Four control replicates (wildtype) and four experimental replicates (Fabp4-Ebf2) mice were analyzed
Project description:Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step in the development of NAFLD. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism to NAFLD and systemic metabolic homeostasis. We show that LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress and damage in response to high fat diets. Furthermore, increased energy expenditure accompanied by enhanced adipose tissue browning was observed in LKO mice. Mechanistically, hepatic CPT1A deficiency actives the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis and the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Thus, our study demonstrates that liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
Project description:The induction of beige/brite adipose cells in white adipose tissue (WAT) is associated with protection against high fat diet-induced obesity and insulin resistance in animals. The helix-loop-helix transcription factor Early B-Cell Factor-2 (EBF2) regulates brown adipose tissue development. We examined the role of EBF2 in beige fat cell biogenesis by comparing transcriptome in wildtype and EBF2-overexpressing mice in the adipose tissue.
