Summary The transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator-1 α (PGC-1α) regulates metabolic genes in skeletal muscle, and contributes substantially to the response of muscle to exercise. Muscle specific PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolic profiling approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a novel small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipose tissue and fatty acid β-oxidation in hepatocytes both in vitro and in vivo through a PPARα mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.

Summary Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we show that the lipoprotein lipase inhibitor Angptl4 protects against the pronounced pro-inflammatory effects of dietary saturated fat. Strikingly, in mice lacking Angptl4, dietary saturated fat induces a severe and ultimately lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in the mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced macrophage foam cell formation, inflammatory gene expression, and chyle-induced activation of the ER stress pathway. The data reveal a novel mechanism in which induction of macrophage Angptl4 by fatty acids serves to reduce postprandial lipid uptake from fatty chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled dietary saturated fat-induced inflammation.

Consumption of specific dietary fatty acids has been shown to influence risk and progression of several chronic diseases, such as cardiovascular disease, obesity, cancer, and arthritis. In recent years, insights into the mechanisms underlying the biological effects of fatty acids have improved considerably and have provided the foundation for the emerging concept of fatty acid sensing, which can be interpreted as the property of fatty acids to influence biological processes by serving as signaling molecules. An important mechanism of fatty acid sensing is via stimulation or inhibition of DNA transcription. Here, we focus on fatty acid sensing via regulation of gene transcription and address the role of peroxisome proliferator-activated receptors, sterol regulatory element binding protein 1, Toll-like receptor 4, G protein-coupled receptors, and other putative mediators.

Key Words: peroxisome proliferator-activated receptor Ⅲ Angptl4 Ⅲ fatty acids Ⅲ gene expression Ⅲ cardiac oxidative stress C ardiac contractility is dependent on the adequate delivery of oxygen and energy substrates to the heart followed by their efficient metabolic degradation to yield ATP. The energy requirements of the contracting heart are primarily met by fatty acid oxidation, with the remainder of energy coming from glucose and lactate.