Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age-and sex-matched recipient mice. By 8-12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet-induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6-knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.

In patients with diabetes, an increased risk of symptomatic heart failure usually develops in the presence of hypertension or ischemic heart disease. However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in diastolic function that can occur in asymptomatic patients with diabetes alone (termed diabetic cardiomyopathy). Evidence of cardiomyopathy has also been demonstrated in animal models of both Type 1 (streptozotocin-induced diabetes) and Type 2 diabetes (Zucker diabetic fatty rats and ob/ob or db/db mice). During insulin resistance or diabetes, the heart rapidly modifies its energy metabolism, resulting in augmented fatty acid and decreased glucose consumption. Accumulating evidence suggests that this alteration of cardiac metabolism plays an important role in the development of cardiomyopathy. Hence, a better understanding of this dysregulation in cardiac substrate utilization during insulin resistance and diabetes could provide information as to potential targets for the treatment of cardiomyopathy. This review is focused on evaluating the acute and chronic regulation and dysregulation of cardiac metabolism in normal and insulin-resistant/diabetic hearts and how these changes could contribute toward the development of cardiomyopathy.

The Akt substrate of 160 kDa (AS160) is phosphorylated on Akt substrate (PAS) motifs in response to insulin and contraction in skeletal muscle, regulating glucose uptake. Here we discovered a dissociation between AS160 protein expression and apparent AS160 PAS phosphorylation among soleus, tibialis anterior, and extensor digitorum longus muscles. Immunodepletion of AS160 in tibialis anterior muscle lysates resulted in minimal depletion of the PAS band at 160 kDa, suggesting the presence of an additional PAS immunoreactive protein. By immunoprecipitation and mass spectrometry, we identified this protein as the AS160 paralog TBC1D1, an obesity candidate gene regulating GLUT4 translocation in adipocytes. TBC1D1 expression was severalfold higher in skeletal muscles compared with all other tissues and was the dominant protein detected by the anti-PAS antibody at 160 kDa in tibialis anterior and extensor digitorum longus but not soleus muscles. In vivo stimulation by insulin, contraction, and the AMP-activated protein kinase (AMPK) activator AICAR increased TBC1D1 PAS phosphorylation. Using mass spectrometry on TBC1D1 from mouse skeletal muscle, we identified several novel phosphorylation sites on TBC1D1 and found the majority were consensus or near consensus sites for AMPK. Semiquantitative analysis of spectra suggested that AICAR caused greater overall phosphorylation of TBC1D1 sites compared with insulin. Purified Akt and AMPK phosphorylated TBC1D1 in vitro, and AMPK, but not Akt, reduced TBC1D1 electrophoretic mobility. TBC1D1 is a major PAS immunoreactive protein in skeletal muscle that is phosphorylated in vivo by insulin, AICAR, and contraction. Both Akt and AMPK phosphorylate TBC1D1, but AMPK may be the more robust regulator.A defining pathology of type 2 diabetes is impaired insulinstimulated glucose uptake in skeletal muscle. Skeletal muscle is the largest tissue in the human body by mass and is the chief site of insulin-stimulated glucose disposal. Insulin stimulation causes translocation of GLUT4 glucose transporters from intracellular regions to the plasma membrane and t-tubule system where they function to import glucose. In individuals with type 2 diabetes, insulin fails to stimulate adequate GLUT4 translocation, resulting in impaired glucose uptake and poor glucose tolerance.Skeletal muscle is unique as an insulin-sensitive tissue because voluntary contraction during exercise causes GLUT4 translocation completely independent of insulin signaling (1, 2). Contraction-stimulated glucose uptake is preserved in the muscle of individuals with type 2 diabetes, thus demonstrating the existence of signaling pathways that circumvent defective components of the insulin signaling pathway (3). If and where insulin-and contraction-stimulated glucose uptake pathways converge have been topics of considerable interest. Recently, the Akt substrate of 160 kDa (AS160) 2 was identified as a mediator of both insulin-and contraction-stimulated glucose uptake and, therefore, a potential nexus for convergent signaling (4, 5).A...

Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissues mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on whole body metabolism, we have generated a mouse model with disruption of the mitochondrial transcription factor A (TFAM) specifically in fat. F-TFKO adipose tissue exhibit decreased mtDNA copy number, altered levels of proteins of the electron transport chain, and perturbed mitochondrial function with decreased Complex I activity and greater oxygen consumption and uncoupling. As a result, F-TFKO mice exhibit higher energy expenditure and are protected from age- and diet-induced obesity, insulin resistance and hepatosteatosis, despite a greater food intake. Thus, TFAM deletion in the adipose tissue increases mitochondrial oxidation that has positive metabolic effects suggesting that regulation of adipose tissue mitochondria may be a potential therapeutic target for the treatment of obesity.