Person:

Schneider, Benjamin Edward

Objective: Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes. Research Design and Methods: We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro. Results: In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA({1c}) marginally (8.01 (\pm) 0.93–7.96 (\pm) 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of (\sim)50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at (\sim)50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling. Conclusions: In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA({1c}) marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.

Objective: To study the day-night variation of omentin-1 levels and assess whether leptin, and/or short-and long-term energy deprivation alter circulating omentin-1 levels via cytokines. Design and Methods Omentin-1 levels were measured hourly in serum samples from six healthy men to evaluate for day-night variation. To study effects of acute energy deprivation and of leptin administration, eight healthy subjects were studied in the fasting state for 72 hours with administration of either placebo or metreleptin in physiological replacement doses. We evaluated the effect of leptin in pharmacological doses on serum omentin-1 and cytokine levels, as well as on omentin-1 levels in ex vivo omental adipose tissue, in fifteen healthy volunteers. To study the effect of chronic energy deprivation and weight loss on omentin-1 levels we followed eighteen obese subjects for 12 months who underwent bariatric surgery. Results: There is no day-night variation in omentin-1 levels. Short-term and chronic energy deprivation as well as ex vivo leptin administration and physiological replacement doses of leptin do not alter omentin-1 levels, whereas pharmacologic doses of metreleptin reduce omentin-1 levels whereas levels of TNF-α receptor II and IL-6 tend to increase. Conclusions: Omentin-1 levels are reduced by pharmacological doses of metreleptin independent of effects on cytokine levels.

OBJECTIVE: Amylin interacts with leptin to alter metabolism. We evaluated, for the first time, amylin- and/or leptin-activated signaling pathways in human peripheral tissues (hPTs). RESEARCH DESIGN AND METHODS: Leptin and amylin signaling studies were performed in vitro in human primary adipocytes (hPAs) and human peripheral blood mononuclear cells (hPBMCs) and ex vivo in human adipose tissue (hAT) from male versus female subjects, obese versus lean subjects, and subjects with subcutaneous versus omental adipose tissue. RESULTS: The long form of leptin receptor was expressed in human tissues and cells studied in ex vivo and in vitro, respectively. Leptin and amylin alone and in combination activate signal transducer and activator of transcription 3 (STAT3), AMP-activated protein kinase, Akt, and extracellular signal-regulated kinase signaling pathways in hAT ex vivo and hPAs and hPBMCs in vitro; all phosphorylation events were saturable at leptin and amylin concentrations of ∼50 and ∼20 ng/ml, respectively. The effects of leptin and amylin on STAT3 phosphorylation in hPAs and hPBMCs in vitro were totally abolished under endoplasmic reticulum stress and/or in the presence of a STAT3 inhibitor. Results similar to those in the in vitro studies were observed in hAT studied ex vivo. CONCLUSIONS: Leptin and amylin activate overlapping intracellular signaling pathways in humans and have additive, but not synergistic, effects in signaling pathways studied in hPTs in vitro and ex vivo.