Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.

Emergence of chronic ‘sterile’ inflammation during obesity in absence of overt infection or autoimmune process is a puzzling phenomenon. The Nod Like Receptor (NLR) family of innate immune cell sensors like the Nlrp3 inflammasome are implicated in recognizing certain non-microbial origin ‘danger–signals’ leading to caspase-1 activation and subsequent IL-1β and IL-18 secretion. We show that reduction in adipose tissue expression of Nlrp3 is coupled with decreased inflammation and improved insulin–sensitivity in obese type-2 diabetic patients. The Nlrp3 inflammasome senses the lipotoxicity–associated ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 prevented the obesity–induced inflammasome activation in fat depots and liver together with enhanced insulin–signalling. Furthermore, elimination of Nlrp3 in obesity reduced IL-18 and adipose tissue IFNγ along with an increase in naïve and reduction in effector adipose tissue T cells. Collectively, these data establish that Nlrp3 inflammasome senses obesity–associated ‘danger–signals’ and contributes to obesity–induced inflammation and insulin–resistance.

Ghrelin is a novel endogenous natural ligand for the growth hormone (GH) secretagogue receptor that has recently been isolated from the rat stomach. Ghrelin administration stimulates GH secretion but also causes weight gain by increasing food intake and reducing fat utilization in rodents. To investigate the possible involvement of ghrelin in the pathogenesis of human obesity, we measured body composition (by dual X-ray absorption) as well as fasting plasma ghrelin concentrations (radioimmunoassay) in 15 Caucasians (8 men and 7 women, 31 ؎ 9 years of age, 92 ؎ 24 kg body wt, and 29؎10% body fat, mean ؎ SD) and 15 Pima Indians (8 men and 7 women, 33 ؎ 5 years of age, 97 ؎ 29 kg body wt, and 30 ؎ 8% body fat). Fasting plasma ghrelin was negatively correlated with percent body fat (r ‫؍‬ -0.45; P ‫؍‬ 0.01), fasting insulin (r ‫؍‬ -0.45; P ‫؍‬ 0.01) and leptin (r ‫؍‬ -0.38; P ‫؍‬ 0.03) concentrations. Plasma ghrelin concentration was decreased in obese Caucasians as compared with lean Caucasians (P < 0.01). Also, fasting plasma ghrelin was lower in Pima Indians, a population with a very high prevalence of obesity, compared with Caucasians (87 ؎ 28 vs. 129 ؎ 34 fmol/ml; P < 0.01). This result did not change after adjustment for fasting plasma insulin concentration. There was no correlation between fasting plasma ghrelin and height. Prospective clinical studies are now needed to establish the role of ghrelin in the pathogenesis of human obesity. Diabetes 50: [707][708][709] 2001 W e recently reported (1) that the gastric hormone ghrelin (2) provides a peripheral signal to the brain that induces adiposity in rodents. To investigate a possible involvement of ghrelin in the pathogenesis of human obesity, we measured endogenous ghrelin concentrations in lean and obese Caucasian and Pima Indian individuals. We hypothesized that 1) obese individuals would present with elevated ghrelin levels that could contribute to the pathogenesis of obesity and 2) Pima Indians, a population with one of the highest reported prevalence rates of obesity and type 2 diabetes in the world, would present with elevated ghrelin levels when compared with Caucasians. RESEARCH DESIGN AND METHODSA total of 15 Caucasian and 15 Pima Indian subjects matched for age, sex, and body weight were divided into lean (n ϭ 7) and obese (n ϭ 8) subgroups (Table 1). Obesity was defined as BMI Ͼ30 kg/m 2 , according to the criteria of both the World Health Organization and the International Obesity Task Force. All participants were between 20 and 50 years of age, nondiabetic according to an oral glucose tolerance test, and healthy according to a physical examination and routine laboratory tests. Subjects were admitted to the research ward of the Clinical Diabetes and Nutrition Section of the National Institutes of Health in Phoenix, Arizona, where they received a weightmaintaining diet (50% carbohydrate, 30% fat, and 20% protein) and abstained from exercise for at least 2 days before the study. The protocol was approved by the Tribal Council of the Gila River In...

Intermittent fasting (IF) improves cardiometabolic health; however, it is unknown whether these effects are due solely to weight loss. We conducted the first supervised controlled feeding trial to test whether IF has benefits independent of weight loss by feeding participants enough food to maintain their weight. Our proof-of-concept study also constitutes the first trial of early time-restricted feeding (eTRF), a form of IF that involves eating early in the day to be in alignment with circadian rhythms in metabolism. Men with prediabetes were randomized to eTRF (6-hr feeding period, with dinner before 3 p.m.) or a control schedule (12-hr feeding period) for 5 weeks and later crossed over to the other schedule. eTRF improved insulin sensitivity, β cell responsiveness, blood pressure, oxidative stress, and appetite. We demonstrate for the first time in humans that eTRF improves some aspects of cardiometabolic health and that IF's effects are not solely due to weight loss.

Insulin resistance is a major risk factor for the development of NIDDM: A low acute insulin response to glucose is an additional but weaker risk factor.

ClinicalTrials.gov Identifier: NCT00099151.

reproducible (coefficient of variation = 2.4%); and (c) even when adjusted for differences in FFM, there is still considerable interperson variability of the daily energy expenditure. A large portion of the variability of 24EE among individuals, independent of differences in body size, was due to variability in the degree of spontaneous physical activity, i.e., "fidgeting," which accounted for 100-800 kcal/d in these subjects.

The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.