Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity.

No-Joon Song,Aejin Lee,Shanvanth Arnipalli,Dean J Mikami,Sabrena F Noria,Ouliana Ziouzenkova,Rumana Yasmeen,Kefeng Yang,Jeffrey W Hazey,Qiwen Shen,Shashi Bhushan Kumar,Jeremy Prokop,Joana Ortega-Anaya,Danah Muhanna,Rafael Jiménez-Flores,Bradley J Needleman

doi:10.3390/cells11030425

No-Joon Song, Aejin Lee + Show 14 more

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https://doi.org/10.3390/cells11030425

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Abstract

The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in Lepob mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in Lepob mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of Lepob mice. EREG/LepR regulated glucose uptake without changes in obesity in Lepob mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in Leprdb mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand.

Highlights

Leptin receptor (LepR, Alias: CD295, or ObR) regulates critical aspects of energy homeostasis, appetite, and notably plays a central role in the regulation of glucose uptake in both peripheral organs and the central nervous system [1,2]
We investigated the glycemic effects of EREG in Lepob mice, which have functional leptin receptor (LepR) but lack leptin
We examined the role of EREG in the activation of downstream signaling pathways associated with epidermal growth factor receptor (EGFR) and LepR in 3T3-L1 cells (Figure 4B)

Summary

Introduction

Leptin receptor (LepR, Alias: CD295, or ObR) regulates critical aspects of energy homeostasis, appetite, and notably plays a central role in the regulation of glucose uptake in both peripheral organs and the central nervous system [1,2]. The malfunction of leptin and/or LepR is among the most widespread metabolic malfunctions associated with genetic, immune, endocrine, and diet-related diseases. Deficiencies in leptin or LepR signaling, or leptin resistance can develop in response to inflammation, endocrine disorders, lipodystrophy, or obesity, which progresses to glucose intolerance and insulin resistance [2,3]. A genetic LepR deficiency in Leprdb mice manifests with obesity, diabetes, hyperglycemia, insulin resistance, as well as aberrant immune responses and reproduction [2]. Leptin deficiency in Lepob mice presents a less severe phenotype than LepR-deficient Leprdb mice [4]. These differences indicate a possible existence of other factors interacting with LepR via direct or indirect mechanisms

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