Abstract
Adipose tissue is an important metabolic organ that integrates a wide array of homeostatic processes and is crucial for whole-body insulin sensitivity and energy metabolism. Brown adipose tissue (BAT) is a key thermogenic tissue with a well-established role in energy expenditure. BAT dissipates energy and protects against both hypothermia and obesity. Thus, BAT stimulation therapy is a rational strategy for the looming pandemic of obesity, whose consequences and comorbidities have a huge impact on the aged. Shc-deficient mice (ShcKO) were previously shown to be lean, insulin sensitive, and resistant to high-fat diet and obesity. We investigated the contribution of BAT to this phenotype. Insulin-dependent BAT glucose uptake was higher in ShcKO mice. Primary ShcKO BAT cells exhibited increased mitochondrial respiration; increased expression of several mitochondrial and lipid-oxidative enzymes was observed in ShcKO BAT. Levels of brown fat-specific markers of differentiation, UCP1, PRDM16, ELOVL3, and Cox8b, were higher in ShcKO BAT. In vitro, Shc knockdown in BAT cell line increased insulin sensitivity and metabolic activity. In vivo, pharmacological stimulation of ShcKO BAT resulted in higher energy expenditure. Conversely, pharmacological inhibition of BAT abolished the improved metabolic parameters, that is the increased insulin sensitivity and glucose tolerance of ShcKO mice. Similarly, in vitro Shc knockdown in BAT cell lines increased their expression of UCP1 and metabolic activity. These data suggest increased BAT activity significantly contributes to the improved metabolic phenotype of ShcKO mice.
Highlights
Obesity is epidemic in the United States; 34% of adults suffer from obesity
It was shown that adult humans retain differentiated brown adipose tissue depots, (Cypess et al, 2009; Virtanen et al, 2009) fostering renewed enthusiasm that brown fat activity could be stimulated in adult humans as an anti-obesity therapy
As Shc has been implicated in adipocyte differentiation (Laurino & Cordera, 1998; Boney et al, 2001; Woldt et al, 2011), we investigated effects of Shc reduction on brown adipose properties in ShcKO mice
Summary
A major consequence is type II diabetes, which is common in the U.S, and 27% of adults over 65 suffer from this problem. The consequences and comorbidities of obesity and diabetes have a massive negative impact on the aged, including increased risk for cardiovascular. Strategies to combat obesity and diabetes are urgently needed and could have a major beneficial impact on the aging population of all developed counties. Brown fat stimulation as an anti-obesity strategy lagged for several years, because it was thought that brown fat was developmentally eliminated after infancy in humans. It was shown that adult humans retain differentiated brown adipose tissue depots, (Cypess et al, 2009; Virtanen et al, 2009) fostering renewed enthusiasm that brown fat activity could be stimulated in adult humans as an anti-obesity therapy
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