The effect of leptin on adipocyte metabolism in leptin-responsive, partially leptin-resistant, and leptin-resistant animals

We consistently find that peripheral infusions of physiological doses of leptin inhibit lipogenesis in leptin-responsive animals. This study determined which aspect of leptin response was lost in fully and partially leptin-resistant animals. Male Wistar rats consumed a low-fat (LF, 10%) or high-fat (HF, 60%) diet for 3 months to generate diet induced obesity and leptin-resistance, which was confirmed by a bolus i.p. injection of 2.5 mg/kg leptin inhibiting 24 h food intake of only low-fat (LF, 10%) fed rats. Subsequently, rats were infused with 70 μg leptin/d or PBS for 11 days. Metabolic changes were measured in liver, epididymal (EPI), and retroperitoneal (RP) fat pads. Results showed leptin had no effect on liver or adipocyte metabolism of the HF-fed rats. In contrast, LF-fed rats were partially leptin-resistant as demonstrated by unexpected increases in liver and RP fatty acid synthesis (FAS), and increased RP basal glucose oxidation. Subsequently, to obtain data from leptin-responsive animals we conducted the same study in Wistars fed LF diet for 3 weeks. We found the expected decrease in RP fatty acid esterification, glucose oxidation, and inhibition of de novo FAS in both EPI and RP pads. These results confirmed that physiological doses of leptin reduce body fat in leptin-responsive animals by inhibiting lipogenesis. There is no effect in leptin resistant rats, but surprisingly, leptin promotes fat gain in animals progressing from leptin-responsiveness to leptin-resistance. Further studies are needed to investigate why leptin increases adipose mass in partially leptin-resistant models. Supported by NIH Grant DK053903.