Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes

Abstract

Metformin is an anti-diabetic drug with anorexigenic properties. The precise cellular mechanisms of its action are not entirely understood. Adipose tissue has recently been recognized as an important endocrine organ that is pivotal for the regulation of insulin resistance and energy homeostasis. Due to its thermogenic capacity brown adipose tissue contributes to the regulation of energy metabolism and is an attractive target tissue for pharmacological approaches to treating insulin resistance and obesity. Leptin is the prototypic adipocyte-derived hormone inducing a negative energy balance. We investigated effects of metformin on adipocyte metabolism, signalling, and leptin secretion in a brown adipocyte model. Metformin acutely stimulated p44/p42 mitogenactivated protein (MAP) kinase in a dose-(3·2-fold at 1 mmol/l, P<0·05) as well as time-dependent (3·8-fold at 5 min, P<0·05) manner. This stimulation was highly selective since phosphorylation of intermediates in the stress kinase, janus kinase (JAK)-signal transducer and activator of transcription (STAT), and phosphatidylinositol (PI) 3-kinase signalling pathways such as p38 MAP kinase, STAT3, and Akt was unaltered. Furthermore, chronic metformin treatment for 12 days dose-dependently inhibited leptin secretion by 35% and 75% at 500 µmol/l and 1 mmol/l metformin respectively (P<0·01). This reduction was not caused by alterations in adipocyte differentiation. Moreover, the impairment in leptin secretion by metformin was reversible within 48 h after removal of the drug. Pharmacological inhibition of p44/p42 MAP kinase prevented the metformin-induced negative effect on leptin secretion. Taken together, our data demonstrate direct acute effects of metformin on adipocyte signalling and endocrine function with robust inhibition of leptin secretion. They suggest a selective molecular mechanism that may contribute to the anorexigenic effect of this antidiabetic compound.

Rosiglitazone and Metformin Have Opposite Effects on Intestinal Absorption of Oligopeptides via the Proton-Dependent PepT1 Transporter

“…at ASPET Journals on May 9, 2018 molpharm.aspetjournals.org reduce leptin levels as was already reported in vitro and in humans (Morin-Papunen et al, 1998;Klein et al, 2004). In addition to the primary function of PepT1 in the supply of nitrogen to the body, the regulation of PepT1 is of importance in the type 2 diabetes mellitus/obesity phenotype because PepT1 is also involved in the feedback regulation of gastrointestinal functions and food intake.…”

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

“…In a brown adipocyte model, metformin dose dependently inhibited leptin secretion through the stimulation of p44/p42 MAPK, independently of the PI3K signal. This selective molecular mechanism was suggested to contribute to an anorexigenic effect of this compound (42). Adiponectin is another adipokine with insulinsensitizing and anti-inflammatory properties.…”

Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms

“…The modulation of other signaling pathways, including MAPK, PKC, and phosphatidylinositol 3-kinase (PI3K)-PKB pathways, has been im- plicated in the cellular effects of metformin (6,33,37,42). As such, we evaluated the role of these pathways in mediating the metabolic response of H9c2 cells to metformin by the use of pharmacological inhibitors.…”