Lipolysis defect in white adipose tissue and rapid weight regain.

Weight regain after weight loss is a well-described phenomenon in both humans and animal models of obesity. Reduced energy expenditure and increased caloric intake are considered the main drivers of weight regain. We hypothesized that adipose tissue with obesity memory (OM) has a tissue-autonomous lipolytic defect, allowing for increased efficiency of lipid storage. We utilized a mouse model of diet-induced obesity, which was subjected to 60% caloric restriction to achieve lean body weight, followed by a short period of high-fat diet (HFD) rechallenge. Age-matched lean mice fed HFD for the first time were used as the control group. Upon rechallenge with HFD, mice with OM had higher respiratory exchange ratios than lean mice with no OM despite comparable body weight, suggesting higher utilization of glucose over fatty acid oxidation. White adipose tissue explants with OM had comparable lipolytic response after caloric restriction; however, reduced functional lipolytic response to norepinephrine was noted as early as 5 days after rechallenge with HFD and was accompanied by reduction in hormone-sensitive lipase serine phosphorylation. The relative lipolytic defect was associated with increased expression of inflammatory genes and a decrease in adrenergic receptor genes, most notably Adrb3. Taken together, white adipose tissue of lean mice with OM shows increased sensitization to HFD compared with white adipose tissue with no OM, rendering it resistant to catecholamine-induced lipolysis. This relative lipolytic defect is tissue-autonomous and could play a role in the rapid weight regain observed after weight loss.

Mangiferin stimulates carbohydrate oxidation and protects against metabolic disorders induced by high-fat diets.

Excessive dietary fat intake causes systemic metabolic toxicity, manifested in weight gain, hyperglycemia, and insulin resistance. In addition, carbohydrate utilization as a fuel is substantially inhibited. Correction or reversal of these effects during high-fat diet (HFD) intake is of exceptional interest in light of widespread occurrence of diet-associated metabolic disorders in global human populations. Here we report that mangiferin (MGF), a natural compound (the predominant constituent of Mangifera indica extract from the plant that produces mango), protected against HFD-induced weight gain, increased aerobic mitochondrial capacity and thermogenesis, and improved glucose and insulin profiles. To obtain mechanistic insight into the basis for these effects, we determined that mice exposed to an HFD combined with MGF exhibited a substantial shift in respiratory quotient from fatty acid toward carbohydrate utilization. MGF treatment significantly increased glucose oxidation in muscle of HFD-fed mice without changing fatty acid oxidation. These results indicate that MGF redirects fuel utilization toward carbohydrates. In cultured C2C12 myotubes, MGF increased glucose and pyruvate oxidation and ATP production without affecting fatty acid oxidation, confirming in vivo and ex vivo effects. Furthermore, MGF inhibited anaerobic metabolism of pyruvate to lactate but enhanced pyruvate oxidation. A key target of MGF appears to be pyruvate dehydrogenase, determined to be activated by MGF in a variety of assays. These findings underscore the therapeutic potential of activation of carbohydrate utilization in correction of metabolic syndrome and highlight the potential of MGF to serve as a model compound that can elicit fuel-switching effects.

The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.

As NAD(+) is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38-both NAD(+) consumers-increases NAD(+) bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD(+) precursor with the ability to increase NAD(+) levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.