Miglitol increases energy expenditure by upregulating uncoupling protein 1 of brown adipose tissue and reduces obesity in dietary-induced obese mice

Satoru Sugimoto,Hisakazu Nakajima,Hajime Hosoi,Kazuki Kodo,Kitaro Kosaka,Jun Mori,Kensuke Matsuo,Hiroshi Ikegaya,Kanji Yoshimoto,Wataru Aoi

doi:10.1186/1743-7075-11-14

Satoru Sugimoto, Hisakazu Nakajima + Show 8 more

Open Access

https://doi.org/10.1186/1743-7075-11-14

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Abstract

BackgroundMiglitol is an oral anti-diabetic drug that acts by inhibiting carbohydrate absorption in the small intestine. Recent studies have shown that miglitol reduces obesity in humans and rodents. However, its mechanisms have remained unclear. The purpose of this study was to determine whether miglitol generates heat by activating uncoupling protein 1 (UCP1), an enzyme involved in thermogenesis, in brown adipose tissue (BAT) in mice.MethodsFour-week-old male C57BL/6 J mice were fed a high-fat diet alone (HF) or a high fat diet plus miglitol (HFM). Oxygen consumption (VO2) was used to estimate metabolic rate. A thermal imaging camera was used to quantify heat generation from interscapular brown adipose tissue. We analyzed the protein and gene expressions of UCP1 and the expressions of four proteins related to β3-adrenergic signaling in the pathway activating UCP1 (protein kinase A (PKA), hormone-sensitive lipase (HSL), p38 α mitogen-activated protein kinase (p38αMAPK) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α)).ResultsAt 8 weeks, body weight, epididymal and subcutaneous white adipose tissue and the HOMA-R value of the HFM mice were significantly less than those of the HF mice. Food intake was not different between the HF and HFM mice. VO2 and BAT temperature were significantly higher in the HFM mice. Miglitol significantly enhanced the gene and protein expressions of UCP1 and the expressions of proteins related to β3-adrenergic signaling.ConclusionsMiglitol’s anti-obesity effect was attributed to increased energy expenditure by upregulating UCP1 in BAT (i.e., by thermogenesis) and to enhancement of β3-adrenergic signaling in BAT.

Highlights

Miglitol is an oral anti-diabetic drug that acts by inhibiting carbohydrate absorption in the small intestine
Our results show that miglitol increased energy expenditure, reduced obesity and enhanced β3-adrenergic signaling and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT)
The body weight of mice fed the high fat diet plus miglitol (HFM mice) (25.8 ± 0.4 g) was significantly less than that of high-fat diet alone (HF) mice (p < 0.05) (Table 1, Figure 1A) even though the two groups consumed the same amount of food energy (Figure 1B, C)

Summary

Introduction

Miglitol is an oral anti-diabetic drug that acts by inhibiting carbohydrate absorption in the small intestine. Recent studies have shown that miglitol reduces obesity in humans and rodents. The purpose of this study was to determine whether miglitol generates heat by activating uncoupling protein 1 (UCP1), an enzyme involved in thermogenesis, in brown adipose tissue (BAT) in mice. Only medicines that inhibit energy intake, such as appetite suppressants and lipid absorption inhibitors, are authorized as anti-obesity drugs by the American Food and Drug Administration (FDA). Whereas white adipose tissue acts to store surplus energy, brown adipose tissue (BAT) expends energy by heat production through uncoupling protein 1 (UCP1) in its mitochondria [2]. Recent studies using positron emission tomography/ computed tomography (PET/CT) have shown that adult humans still possess functional BAT. BAT has received much attention as a target of obesity treatment [3,4,5,6,7]

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