leptin and 3-aminoisobutyric-acid

Beta-aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this beta-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals.

Topics: Aminoisobutyric Acids; Animals; Homeostasis; Humans; Leptin; Lipid Metabolism; Mice; Mice, Obese; Obesity

We studied the effect of bacterial pathogen-associated molecular patterns and myokines on the secretion of adipokines by mesenchymal stem cells (MSC) and products of their adipogenic differentiation. The secretion of adiponectin, adipsin, leptin, and insulin by adipogenically differentiated cell cultures was quantitatively determined using multiplex ELISA. MSC obtained from the stromal vascular fraction of human subcutaneous adipose tissue were shown to secrete a known adipokine adipsin. The ability of white adipocytes to secrete significant amounts of insulin (in vitro) has been shown for the first time. Control cultures of white adipocytes secreted much higher levels of adiponectin, leptin, and insulin when compared to other adipocytes cultures. On the other hand, beige and brown adipocyte cultures secreted more adipsin than white adipocyte cultures. The influence of myokine β-aminoisobutyric acid on the secretion of adipsin in MSC, white, beige, and brown adipocytes was also studied.

Topics: Adipocytes, Beige; Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipokines; Adiponectin; Adipose Tissue, Brown; Aminoisobutyric Acids; Cell Differentiation; Complement Factor D; Flagellin; Gene Expression Regulation; Humans; Insulin; Leptin; Lipectomy; Lipopolysaccharides; Mesenchymal Stem Cells; Organ Specificity; Primary Cell Culture

Beta-Aminoisobutyric acid (BAIBA), a thymine catabolite, increases fatty acid oxidation (FAO) in liver and reduces the gain of body fat mass in Swiss (lean) mice fed a standard chow. We determined whether BAIBA could prevent obesity and related metabolic disorders in different murine models. To this end, BAIBA (100 or 500 mg/kg/day) was administered for 4 months in mice totally deficient in leptin (ob/ob). BAIBA (100 mg/kg/day) was also given for 4 months in wild-type (+/+) mice and mice partially deficient in leptin (ob/+) fed a high-calorie (HC) diet. BAIBA did not limit obesity and hepatic steatosis in ob/ob mice, but reduced liver cytolysis and inflammation. In ob/+ mice fed the HC diet, BAIBA fully prevented, or limited, the gain of body fat, steatosis and necroinflammation, glucose intolerance, and hypertriglyceridemia. Plasma beta-hydroxybutyrate was increased, whereas expression of carnitine palmitoyltransferase-1 was augmented in liver and white adipose tissue. Acetyl-CoA carboxylase was more phosphorylated, and de novo lipogenesis was less induced in liver. These favorable effects of BAIBA in ob/+ mice were associated with a restoration of plasma leptin levels. The reduction of body adiposity afforded by BAIBA was less marked in +/+ mice. Finally, BAIBA significantly stimulated the secretion of leptin in isolated ob/+ adipose cells, but not in +/+ cells. Thus, BAIBA could limit triglyceride accretion in tissues through a leptin-dependent stimulation of FAO. As partial leptin deficiency is not uncommon in the general population, supplementation with BAIBA may help to prevent diet-induced obesity and related metabolic disorders in low leptin secretors.

Topics: Alanine Transaminase; Aminoisobutyric Acids; Animals; Antioxidants; Blood Glucose; Body Composition; Cholesterol; Dietary Fats; Fatty Liver; Glucose Tolerance Test; L-Lactate Dehydrogenase; Leptin; Male; Mice; Mice, Inbred C3H; Mice, Obese; Obesity; Rats; Rats, Sprague-Dawley; Triglycerides

Stavudine (d4T), a nucleoside reverse-transcriptase inhibitor (NRTI), can induce lipoatrophy, fatty liver, hyperlactataemia and abnormal liver tests. NRTI toxicity is usually ascribed to mitochondrial DNA (mtDNA) depletion and impaired mitochondrial respiration. However, NRTIs could have effects unrelated to mtDNA. Recently, we reported that 100 mg/kg/day of d4T stimulated fatty acid oxidation (FAO) in mouse liver, and reduced body fatness without depleting white adipose tissue (WAT) mtDNA. We hypothesized that higher d4T doses could further reduce adiposity, while inhibiting hepatic FAO.. Mice were treated for 2 weeks with d4T (500 mg/kg/day), L-carnitine (200 mg/kg/day) or both drugs concomitantly. Body fatness was assessed by dual energy X-ray absorptiometry, and investigations were performed in plasma, liver, muscle and WAT.. D4T reduced the gain of body adiposity, WAT leptin, whole body FAO and plasma ketone bodies, and increased liver triglycerides and plasma aminotransferases with mild ultrastructural abnormalities in hepatocytes. Plasma lactate and respiratory chain activities in tissues were unchanged. Stearoyl-CoA desaturase (SCD-1), an enzyme negatively regulated by leptin, was overexpressed in liver. High doses of beta-aminoisobutyric acid (BAIBA), a d4T catabolite, increased plasma ketone bodies. Although L-carnitine did not correct body adiposity, it prevented d4T-induced impairment of FAO and liver abnormalities.. D4T overdosage triggers fat wasting, leptin insufficiency and mild liver damage, without causing respiratory chain dysfunction. Overexpression of SCD-1 reduces fatty acid oxidation and overcomes the stimulating effect of BAIBA on hepatic FAO. L-carnitine does not correct leptin insufficiency but prevents d4T-induced impairment of FAO and liver damage.

Topics: Adipose Tissue, White; Administration, Oral; Aminoisobutyric Acids; Animals; Carnitine; Chemical and Drug Induced Liver Injury; Fatty Acids; Hepatocytes; Ketone Bodies; Leptin; Lipodystrophy; Liver; Liver Diseases; Male; Mice; Mitochondria, Liver; Reverse Transcriptase Inhibitors; Stavudine; Stearoyl-CoA Desaturase; Transaminases; Vitamin B Complex; Wasting Syndrome