Person:

Liu, Xiaowen

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.

Background/Objectives: Obesity is characterized by chronic inflammation and immune dysregulation, as well as insulin resistance, but the link between obesity and adaptive immunity remains to be fully studied. Methods: To elucidate the role of adaptive immunity on body composition, glucose homeostasis, and inflammation, recombination-activating gene 1 knockout (Rag1-/-) mice, without mature T lymphocytes or B-lymphocytes, were maintained on a low (LFD) or high fat diet (HFD) for 11 weeks. Results: Rag1-/- mice fed HFD gained significantly more weight and had increased body fat compared to wild type. Downregulation of energy expenditure as well as brown fat UCP-1 and UCP-3 gene expression were noticed in HFD fed Rag1-/- mice compared to LFD. HFD mice had significantly decreased energy intake compared to LFD mice, consistent with decreased AgRP and increased POMC gene expressions in the hypothalamus. Moreover, compared to wild type, Rag1-/- mice had lower IL-4 levels, a cytokine recently found to induce browning in white adipocytes, and higher IL-12 levels in HFD fed Rag1-/- mice. Despite that HFD Rag1-/- mice were more obese, they had similar glucose, insulin, and adiponectin levels, while leptin was marginally increased. Conclusions: Mice with deficiency in adaptive immunity are obese, partly due to decreased energy expenditure, but are metabolically normal, suggesting that mature lymphocytes play necessary roles in the development of obesity-related metabolic dysregulation.