Adipose tissue insulin resistance due to loss of PI3K p110α leads to decreased energy expenditure and obesity

Abstract

Adipose tissue insulin resistance due to loss of PI3K p110␣ leads to decreased energy expenditure and obesity. Am J Physiol Endocrinol Metab 306: E1205-E1216, 2014. First published April 8, 2014 doi:10.1152/ajpendo.00625.2013.-Adipose tissue is a highly insulin-responsive organ that contributes to metabolic regulation. Insulin resistance in the adipose tissue affects systemic lipid and glucose homeostasis. Phosphoinositide 3-kinase (PI3K) mediates downstream insulin signaling in adipose tissue, but its physiological role in vivo remains unclear. Using Cre recombinase driven by the aP2 promoter, we created mice that lack the class 1A PI3K catalytic subunit p110␣ or p110␤ specifically in the white and brown adipose tissue. The loss of p110␣, not p110␤, resulted in increased adiposity, glucose intolerance and liver steatosis. Mice lacking p110␣ in adipose tissue exhibited a decrease in energy expenditure but no change in food intake or activity compared with control animals. This low energy expenditure is a consequence of low cellular respiration in the brown adipocytes caused by a decrease in expression of key mitochondrial genes including uncoupling protein-1. These results illustrate a critical role of p110␣ in the regulation of energy expenditure through modulation of cellular respiration in the brown adipose tissue and suggest that compromised insulin signaling in adipose tissue might be involved in the onset of obesity. phosphoinositide 3-kinase; obesity; insulin; energy expenditure; brown adipose tissue OBESITY IS A PANDEMIC that already affects over 10% of the world's population (3). Obesity is tightly linked to the onset of type 2 diabetes and metabolic syndrome and contributes to increased mortality rates (1, 44). Despite its high prevalence, the underlying causes of obesity are not fully understood. The leptin receptor mutant db/db mouse is a well-studied model of severe obesity, diabetes, and dyslipidemia (27); however, its relevance to the human disorder is limited, since the vast majority of obese patients do not have leptin receptor mutations (21). Insulin receptor (IR) knockout mice have provided unique insight into how insulin resistance in the liver, muscle or adipose tissue affects adiposity and glucose homeostasis. Muscle-specific IR knockout (MIRKO) mice exhibited normal glucose tolerance associated with increased adiposity, whereas mice with liver-specific ablation of the IR (LIRKO) were glucose intolerant and had normal fat mass (10, 39). The fat-specific IR knockout mouse (FIRKO) exhibited reduced adiposity and normal or improved glucose tolerance (7).Adipose tissue is a highly insulin-responsive organ that contributes to the regulation of whole body glucose and lipid homeostasis. White adipose tissue (WAT) stores triglycerides, which are broken down to produce energy during times of caloric need. WAT also acts as an endocrine organ by secreting adipokines such as leptin, which acts in energy sensing and pubertal development (36). Brown adipose tissue (BAT) is responsible for the production...

Energy balancing by fat Pik3ca

“…Mice with reduced PI3K activity in the adipose tissue consumed the same number of calories and exhibited the same ambulatory activity as the control animals, yet they had lower energy expenditure when compared to their lean controls. 11 This lack of balance between caloric intake and expenditure likely contributes to the a¡/¡ obese phenotype. We provided evidence that the reduction in energy expenditure in the a¡/¡ mouse is due at least in part to decreased BAT energy expenditure as a result of reduced expression of many key mitochondrial-specific and thermogenic genes including the classic BAT marker UCP-1 (uncoupling protein-1).…”

“…11 Impaired glucose tolerance and high fasting serum insulin levels were further evidence of systemic metabolic disorders caused by adiposespecific loss of p110a. These results strongly indicate that p110a signaling in the adipose tissues regulates systemic insulin sensitivity.…”

“…11 To determine if impaired BAT was a direct cause of obesity in the a¡/¡ mice, we measured UCP-1 as a marker for BAT respiration. We did not see a difference in UCP-1 expression in BAT from a¡/¡ vs. control mice at 3-4 weeks of age, before the divergence in body weight.…”

“…11 The broad spectrum of genes affected by reduced p110a expression in BAT adds to the known importance of transcriptional regulation by the insulin signaling pathway. 11 The reduced respiration of a¡/¡ BAT is likely a result of a global reduction in respiratory gene expression rather than loss of one target such as UCP-1.…”

“…11 The broad spectrum of genes affected by reduced p110a expression in BAT adds to the known importance of transcriptional regulation by the insulin signaling pathway. 11 The reduced respiration of a¡/¡ BAT is likely a result of a global reduction in respiratory gene expression rather than loss of one target such as UCP-1. Reduced energy expenditure in the a¡/¡ mouse without any alterations in food intake or activity results in an energy surplus exemplified by elevated serum lipids including free fatty acids (FFAs) which cause lipotoxicity in peripheral tissues (Fig.…”