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Abstract
Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFβ signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity.
Highlights
Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals
Our data demonstrate that sLR11 is able to bind to bone morphogenetic protein (BMP) receptors and suppress thermogenic signalling via suppression of downstream Smad protein phosphorylation
The expression profile of Lr11 and serum levels of sLR11 in mice increase at times of increased thermogenesis, suggesting a regulatory role of sLR11 in preventing excessive energy wastage. sLR11 levels correlate with adiposity in humans, leading us to conclude that sLR11 may be an important negative regulator of adipose tissue energy expenditure, which is dysregulated in obesity, potentially compromising metabolic responses to nutritional stimuli
Summary
Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Levels of detectable BAT correlate negatively with age, body mass index (BMI) and diabetes[7], and using intermittent cold exposure to increase amounts of BAT is sufficient to increase post-prandial energy expenditure and improve insulin sensitivity[8]. These findings support the hypothesis that thermogenesis in BAT is an important factor contributing to human metabolism. SLR11 levels correlate with adiposity in humans, leading us to conclude that sLR11 may be an important negative regulator of adipose tissue energy expenditure, which is dysregulated in obesity, potentially compromising metabolic responses to nutritional stimuli The expression profile of Lr11 and serum levels of sLR11 in mice increase at times of increased thermogenesis, suggesting a regulatory role of sLR11 in preventing excessive energy wastage. sLR11 levels correlate with adiposity in humans, leading us to conclude that sLR11 may be an important negative regulator of adipose tissue energy expenditure, which is dysregulated in obesity, potentially compromising metabolic responses to nutritional stimuli
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