Adipocyte Apoptosis, a Link between Obesity, Insulin Resistance, and Hepatic Steatosis

Philip R. Schauer,Michael P. Berk,Naim Alkhouri,Samjhana Thapaliya,Laura J. Dixon,Sangeeta Kashyap,Ariel E. Feldstein,Agnieszka Gornicka

doi:10.1074/jbc.m109.074252

Philip R. Schauer, Michael P. Berk

Open Access

https://doi.org/10.1074/jbc.m109.074252

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Abstract

Adipocyte death has been reported in both obese humans and rodents. However, its role in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity has not been studied. We now show using real-time reverse transcription-PCR arrays that adipose tissue of obese mice display a pro-apoptotic phenotype. Moreover, caspase activation and adipocyte apoptosis were markedly increased in adipose tissue from both mice with diet-induced obesity and obese humans. These changes were associated with activation of both the extrinsic, death receptor-mediated, and intrinsic, mitochondrial-mediated pathways of apoptosis. Genetic inactivation of Bid, a key pro-apoptotic molecule that serves as a link between these two cell death pathways, significantly reduced caspase activation, adipocyte apoptosis, prevented adipose tissue macrophage infiltration, and protected against the development of systemic insulin resistance and hepatic steatosis independent of body weight. These data strongly suggest that adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis associated with obesity in both mice and humans. Inhibition of adipocyte apoptosis may be a new therapeutic strategy for the treatment of obesity-associated metabolic complications.

Highlights

In both humans and rodents, adipose tissue macrophages (ATM) accumulate in AT with increasing body weight, and preventing the accumulation of ATM protects against the obesity-associated inflammatory state and development of insulin resistance (10 –13)
We examined the effects of the positive cells and degree of insulin resistance, steatosis, and different diets on systemic insulin resistance, lipid profile, and ATM infiltration
By Western blot analysis, we found that Fas and FasL protein expression was significantly increased in the AT of obese animals compared with lean mice (Fig. 4A). This observation was further supported by Fas and FasL immunostaining in adipose tissue of mice on the high fat (HFAT) and HSD diet. These changes were associated with activation of Fas signaling as shown by detection of the activated form of caspase 8 and a marked increase in the cleaved, truncated Bid, a BH3only protein of the Bcl-2 family that plays a central role as a regulator of the interaction between the extrinsic and the intrinsic pathways of apoptosis (Fig. 4A)

Summary

EXPERIMENTAL PROCEDURES

Male C57BL/6 mice, 20 to 25 g of body weight, were purchased from Jackson Laboratory. Mice were placed on two different diets that allow us to study the spectrum of human obesity. Mice were fed either a high fat (HFAT) diet (consisting of 42% Kcal from fat, 42.7% carbohydrate, 15.2% protein, 4% mineral mixture, TD 88137, Teklad Mills, Madison, WI), or a high sucrose (HSD) diet (consisting of 65% sucrose, 20% casein, 5% corn oil, 4% mineral mixture, TD 98090, Teklad Mills, Madison, WI) (n ϭ 5– 6 in each group) that result in obesity, hepatic steatosis, and systemic insulin resistance (20 –22). Control mice were fed a standard diet consisting of 5% fat (TD 2918, Teklad Mills, Madison, WI) (n ϭ 6). Animals in each group were sacrified after 6 weeks on respective diets

Adipocyte Apoptosis and Insulin Resistance

Findings

RESULTS