Serum leptin concentrations are correlated with the percentage of body fat, suggesting that most obese persons are insensitive to endogenous leptin production.

No abstract

We investigated the response of leptin to short-term fasting and refeeding in humans. A mild decline in subcutaneous adipocyte ob gene mRNA and a marked fall in serum leptin were observed after 36 and 60 h of fasting. The dynamics of the leptin decline and rise were further substantiated in a 6-day study consisting of a 36-h baseline period, followed by 36-h fast, and a subsequent refeeding with normal diet. Leptin began a steady decline from the baseline values after 12 h of fasting, reaching a nadir at 36 h. The subsequent restoration of normal food intake was associated with a prompt leptin rise and a return to baseline values 24 h later. When responses of leptin to fasting and refeeding were compared with that of glucose, insulin, fatty acids, and ketones, a reverse relationship between leptin and beta-OH-butyrate was found. Consequently, we tested whether the reciprocal responses represented a causal relationship between leptin and beta-OH-butyrate. Small amounts of infused glucose equal to the estimated contribution of gluconeogenesis, which was sufficient to prevent rise in ketogenesis, also prevented a fall in leptin. The infusion of beta-OH-butyrate to produce hyperketonemia of the same magnitude as after a 36-h fast had no effect on leptin. The study indicates that one of the adaptive physiological responses to fasting is a fall in serum leptin. Although the mediator that brings about this effect remains unknown, it appears to be neither insulin nor ketones.

This study was undertaken to investigate the changes in obesity (OB) gene expression and production of leptin in response to insulin in vitro and in vivo under euglycemic and hyperglycemic conditions in humans. Three protocols were used: 1) euglycemic clamp with insulin infusion rates at 40, 120, 300, and 1,200 mU / m / min carried out for up to 5 h performed in 16 normal lean individuals, 30 obese individuals, and 31 patients with NIDDM; 2) 64-to 72-h hyperglycemic (glucose 12.6 mmol/l) clamp performed on 5 lean individuals; 3) long-term (96-h) primary culture of isolated abdominal adipocytes in the presence and absence of 100 nmol/l insulin. Short-term hyperinsulinemia in the range of 80 to > 10,000 microU/ml had no effect on circulating levels of leptin. During the prolonged hyperglycemic clamp, a rise in leptin was observed during the last 24 h of the study (P < 0.001). In the presence of insulin in vitro, OB gene expression increased at 72 h (P < 0.01), followed by an increase in leptin released to the medium (P < 0.001). In summary, insulin does not stimulate leptin production acutely; however, a long-term effect of insulin on leptin production could be demonstrated both in vivo and in vitro. These data suggest that insulin regulates OB gene expression and leptin production indirectly, probably through its trophic effect on adipocytes.

Obese (ob) gene expression in abdominal subcutaneous adipocytes from lean and obese humans was examined. The full coding region of the ob gene was isolated from a human adipocyte cDNA library. Translation of the insert confirmed the reported amino acid sequence. There was no difference in the sequence of an reverse transcription PCR product of the coding region from five lean and five obese subjects. The nonsense mutation in the ob mouse which results in the conversion of arginine 105 to a stop codon was not present in human obesity. In all 10 human cDNAs, arginine 105 was encoded by CGG, consequently two nucleotide substitutions would be required to result in a stop codon. To compare the amount of ob gene expression in lean and obese individuals, radiolabed primer was used in the PCR reaction with (Iactin as a control. There was 72% more ob gene expression (P < 0.01) in eight obese subjects (body mass index, BMI = 42.8±2.7) compared to eight lean controls (BMI = 22.4±0.8). Regression analysis indicated a positive correlation between BMI and the amount of ob message (P < 0.005). There was no difference in the amount of ,B-actin expression in the two groups. These results provide evidence that ob gene expression is increased in human obesity; furthermore, the mutations present in the mouse ob gene were not detected in the human mRNA population. (J. Clin. Invest. 1995. 95:2986-2988