In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes1. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity2. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor3,4. Nicotinamide is a precursor of NAD+, an important cofactor linking cellular redox states with energy metabolism5. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation6. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine–spermine N1-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism7,8. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD+ levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD+-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

Context: Zinc-a2-glycoprotein (ZAG) was found to influence lipolysis in adipose tissue and has recently been proposed as a candidate factor in the regulation of body weight. Objective: To elucidate the association of serum ZAG level with body weight and percentage of body fat in normal, obese subjects and high-fat diet (HFD)-induced obese mice. Design: The relationship between serum ZAG and obesity-related parameters was studied in 44 human subjects and 36 mice fed standard food and HFD. Furthermore, the effects of ZAG overexpression on adipose tissue of mice was also evaluated by using a liposome transfection method. Results: Serum ZAG level was significantly lower in obese patients and obese mice in comparison to that in people and mice with normal weight. The further statistical analysis demonstrated that ZAG level was negatively correlated with body weight (r ¼ À0.62, Po0.001), body mass index (r ¼ À0.64, Po0.001), waist circumference(r ¼ À0.68, Po0.001), hip circumference (r ¼ À0.60, Po0.001), percentage of body fat (r ¼ À0.52, P ¼ 0.03) and fat mass(r ¼ À0.59, P ¼ 0.01) in human subjects after adjustment for age and sex. Furthermore, ZAG overexpression in mice reduced body weight and the percentage of epididymal fat. The decreased FAS, ACC1 and DGAT mRNA and the increased HSL mRNA were also observed in epididymal adipose tissue in ZAG overexpression mice. Conclusion: ZAG is closely linked to obesity. Serum ZAG level is inversely associated with body weight and percentage of body fat. The action of ZAG is associated with downregulated lipogenic enzymes and upregulated lipolytic enzyme expressions in adipose tissue of mice.

PurposeTo determine serum insulin-like growth factor 1 (IGF-I) levels in healthy Chinese adults, establish reference ranges for serum IGF-I levels and observe the effects of age, sex, body mass index (BMI) and geographical region on serum IGF-I levels.MethodsIn total, 2791 healthy adults (1339 males and 1452 females) from the north (Beijing) and south (Guizhou Province) of China were recruited following a questionnaire survey, physical examination and laboratory examination. Both sexes were divided into 13 groups according to age (18, 19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69 and ≥70 years). The serum IGF-I levels were measured by performing a chemiluminescent assay (Immulite 2000®), and the LMS (Lambda-Mu-Sigma) method was applied to construct smooth centile curves of age-specific IGF-I levels.ResultsSerum IGF-I levels in the adults gradually decreased with increasing age from 18 to 70 years in both the male and female participants. Although the decrease in the level of IGF-1 was more pronounced in females than in males, no significant difference was observed between the sexes, except in the 60- to 64-year-old age group (P = 0.0329). The multiple linear regression model showed that there was an inverse relationship between the serum IGF-I level and BMI (P<0.001), and the serum IGF-I level in the Guizhou population was higher than that in the Beijing population (P<0.05).ConclusionThe normal reference ranges for age- and sex-specific serum IGF-I levels were established for the first time in a large sample of Chinese adults. The serum IGF-I levels were significantly influenced by age, BMI and geographical region.