Identification and Saturable Nature of Signaling Pathways Induced by Metreleptin in Humans: Comparative Evaluation of In Vivo, Ex Vivo, and In Vitro Administration

Abstract

Signaling pathways activated by leptin in metabolically important organs have largely been studied only in animal and/or cell culture studies. In this study, we examined whether leptin has similar effects in human peripheral tissues in vivo, ex vivo, and in vitro and whether the response would be different in lean and obese humans. For in vivo leptin signaling, metreleptin was administered and muscle, adipose tissue, and peripheral blood mononuclear cells were taken for analysis of signal activation. Experiments were also done ex vivo and with primary cultured cells in vitro. The signal activation was compared between male versus female and obese versus lean humans. Acute in vivo, ex vivo, and/or in vitro metreleptin administration similarly activated STAT3, AMPK, ERK1/2, Akt, mTOR, NF-κB, and/or IKKα/β without any differences between male versus female and obese versus lean subjects. All signaling pathways were saturable at ∼30–50 ng/mL, consistent with the clinical evidence showing no additional effect(s) in obese subjects who already have high levels of leptin. Our data provide novel information on downstream effectors of metreleptin action in humans that may have therapeutic implications.

Revealing the role of the human blood plasma proteome in obesity using genetic drivers

“…Three proteins were targets for at least one existing drug that has completed phase II clinical trials (Supplementary Data 15 ). Drugs likely for treating obesity included Metreleptin 31 , which targets leptin receptors, to treat complications of leptin deficiency in individuals with congenital or acquired lipodystrophy. Another drug, Pegvisomant 32 , is a highly selective growth hormone (GH) receptor antagonist that is used to treat acromegaly by the production of IGF-1 which is the main mediator of GH activity.…”

From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century

“…It has been suggested that the lack of leptin efficacy in human obesity is due to the development of central leptin resistance or tolerance in parallel with increased circulating leptin levels upon and before obesity development [21]. Leptin signaling pathways, the abnormality of which may eventually lead to the development of leptin resistance, have only recently started to be studied in humans [116][117][118][119][120][121]. In the search for agents that may restore leptin sensitivity, amylin (pramlintide) has been shown to induce weight loss in obese rodent models and humans when given together with leptin [122].…”

GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans

“…as Janus kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) (21,22,23), insulin receptor substrate (IRS)-phosphatidylinositol 3 kinase (PI3K) (24), SH2-containing protein tyrosine phosphatase 2 (SHP2)-mitogen-activated protein kinase (MAPK) (25) and 5′ adenosine monophosphate activated protein kinase (AMPK) -acetyl-CoA carboxylase (ACC) (26). The aforementioned molecular signaling pathways regulate energy homeostasis, anorectic/orexigenic pathways, glucose and fatty acid metabolism, insulin secretion and activation of cellular proliferation pathways (21,24,27,28).…”