Efficacy of metreleptin in obese patients with type 2 diabetes: Cellular and molecular pathways underlying leptin tolerance

Hyun Seuk Moon, Giuseppe Matarese, Aoife M. Brennan, John P. Chamberland, Xiaowen Liu, Christina G. Fiorenza, Geetha H. Mylvaganam, Luisa Abanni, Fortunata Carbone, Catherine J. Williams, Alex M. De Paoli, Benjamin E. Schneider, Christos S. Mantzoros

Research output: Contribution to journalArticle

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Abstract

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 HbA1c marginally (8.01 ± 0.93-7.96 ± 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 ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ;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 HbA1c 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.

Original languageEnglish (US)
Pages (from-to)1647-1656
Number of pages10
JournalDiabetes
Volume60
Issue number6
DOIs
StatePublished - Jun 1 2011

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Leptin
Type 2 Diabetes Mellitus
Endoplasmic Reticulum Stress
Body Weight
Lipodystrophy
Leptin Receptors
metreleptin
Adipocytes
Adipose Tissue
Weight Loss
Blood Cells
Research Design
Randomized Controlled Trials
Placebos
Phosphorylation
Antibodies

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Moon, H. S., Matarese, G., Brennan, A. M., Chamberland, J. P., Liu, X., Fiorenza, C. G., ... Mantzoros, C. S. (2011). Efficacy of metreleptin in obese patients with type 2 diabetes: Cellular and molecular pathways underlying leptin tolerance. Diabetes, 60(6), 1647-1656. https://doi.org/10.2337/db10-1791

Efficacy of metreleptin in obese patients with type 2 diabetes : Cellular and molecular pathways underlying leptin tolerance. / Moon, Hyun Seuk; Matarese, Giuseppe; Brennan, Aoife M.; Chamberland, John P.; Liu, Xiaowen; Fiorenza, Christina G.; Mylvaganam, Geetha H.; Abanni, Luisa; Carbone, Fortunata; Williams, Catherine J.; De Paoli, Alex M.; Schneider, Benjamin E.; Mantzoros, Christos S.

In: Diabetes, Vol. 60, No. 6, 01.06.2011, p. 1647-1656.

Research output: Contribution to journalArticle

Moon, HS, Matarese, G, Brennan, AM, Chamberland, JP, Liu, X, Fiorenza, CG, Mylvaganam, GH, Abanni, L, Carbone, F, Williams, CJ, De Paoli, AM, Schneider, BE & Mantzoros, CS 2011, 'Efficacy of metreleptin in obese patients with type 2 diabetes: Cellular and molecular pathways underlying leptin tolerance', Diabetes, vol. 60, no. 6, pp. 1647-1656. https://doi.org/10.2337/db10-1791
Moon, Hyun Seuk ; Matarese, Giuseppe ; Brennan, Aoife M. ; Chamberland, John P. ; Liu, Xiaowen ; Fiorenza, Christina G. ; Mylvaganam, Geetha H. ; Abanni, Luisa ; Carbone, Fortunata ; Williams, Catherine J. ; De Paoli, Alex M. ; Schneider, Benjamin E. ; Mantzoros, Christos S. / Efficacy of metreleptin in obese patients with type 2 diabetes : Cellular and molecular pathways underlying leptin tolerance. In: Diabetes. 2011 ; Vol. 60, No. 6. pp. 1647-1656.
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T1 - Efficacy of metreleptin in obese patients with type 2 diabetes

T2 - Cellular and molecular pathways underlying leptin tolerance

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AU - Matarese, Giuseppe

AU - Brennan, Aoife M.

AU - Chamberland, John P.

AU - Liu, Xiaowen

AU - Fiorenza, Christina G.

AU - Mylvaganam, Geetha H.

AU - Abanni, Luisa

AU - Carbone, Fortunata

AU - Williams, Catherine J.

AU - De Paoli, Alex M.

AU - Schneider, Benjamin E.

AU - Mantzoros, Christos S.

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N2 - 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 HbA1c marginally (8.01 ± 0.93-7.96 ± 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 ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ;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 HbA1c 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.

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