Treatment with FGFR2-IIIc monoclonal antibody suppresses weight gain and adiposity in KKAy mice.

K Nonogaki,T Yamazaki,T Kaji,Mari Murakami

doi:10.1038/nutd.2016.41

Abstract

Expression of β-Kotho, fibroblast growth factor receptor (FGFR)-1c and 2c, which bind FGF21, is decreased in the white adipose tissue of obese mice. The aim of the present study was to determine the role of FGFR2c in the development of obesity and diabetes in KKAy mice. Treatment with mouse monoclonal FGFR2-IIIc antibody (0.5 mg kg−1) significantly suppressed body weight gain and epididymal white adipose tissue weight in individually housed KKAy mice while having no effect on daily food intake. In addition, treatment with FGFR2-IIIc antibody significantly increased plasma-free fatty acid levels while having no effect on blood glucose or plasma FGF21 levels. Moreover, treatment with FGFR2-IIIc antibody had no significant effect on the expression of uncoupling protein-1, uncoupling protein-2 or peroxisome proliferator-activated receptor-γ coactivator 1α in the epididymal white adipose tissue. The treatment with FGFR2-IIIc antibody had no significant effects on daily food intake and body weight gain in individually housed KK mice. These findings suggest that FGFR2-IIIc upregulates the adiposity induced by social isolation in KKAy mice, and that decreased expression and/or function of FGFR2c might be a compensatory response to enhanced adiposity. Inhibition of FGFR2-IIIc function might be a novel therapeutic approach for obesity.

Highlights

To determine the role of FGFR2c in the development of obesity and type 2 diabetes induced by social isolation, we examined the effect of mouse FGFR2-IIIc monoclonal antibody on food intake, body weight changes, epididymal white adipose tissue (WAT), blood glucose, and plasma-free fatty acids and Fibroblast growth factor 21 (FGF21) levels, and the expression of uncoupling protein-1 (UCP-1), UCP-2 and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) in the eWAT of individually housed KKAy mice
Intraperitoneal administration of FGFR2-IIIc antibody (0.5 mg kg − 1) significantly suppressed body weight gain in individually housed KKAy mice compared with the saline control group (Figure 1a), while having no effect on daily food intake (Figure 1b)
Total RNA was isolated from mouse eWAT using the RNeasy Plus Universal Midi kit (Qiagen, Hilden, Germany) according to the manufacturer’s directions. cDNA synthesis was performed using a cantly decreased eWAT (Figure 2a) and increased plasma FFA levels (Figure 2b) in individually housed KKAy mice compared with the saline controls, while having no significant effect on blood

Summary

Introduction

FGF21 administration increases energy expenditure, insulin sensitivity and weight loss, and normalizes glucose and lipid levels in obese and insulin-resistant rodents.[1,6,7,8]. Circulating FGF21 levels, are elevated in obese rodents[9,10] and humans[11] and the expression of β-Kotho, FGF receptor (FGFR)-1c and 2c in white adipose tissue (WAT) is decreased in obese mice.[10] Adipose-specific FGFR1 knockout mice exhibit a normal body weight and physiological functions, but not the FGF21 treatment-induced decrease in body weight, plasma glucose, insulin and triglyceride observed in wild-type mice.[12,13] On the other hand, adipose-specific FGFR2 knockout mice display hypertrophic adipocytes in the mesenteric WAT but not in the subcutaneous WAT.[14] The role of FGFR2c in the development of obesity and type 2 diabetes, remains unclear. Social isolation promotes obesity due to the primary decreased energy expenditure and the insulin-independent diabetes associated with increased expression of hepatic gluconeogenic genes in KKAy mice.[15]

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