Massage School – a learning environment to help fight diabetes & obesity?
Obesity and diabetes are epidemic in Western societies and account for at least 1/10th of health care expenditures nationwide. The reasons for this are complex; however, it is clear that there is wide variation in individual susceptibility to our obesogenic environment. Our fundamental hypothesis is that the regulation of metabolism in peripheral tissues, specifically skeletal muscle, determines susceptibility to our rich environment and ultimately the common chronic diseases diabetes and cardiovascular disease. In the clinic, we aim to understand the control of fatty acid metabolism but also test novel therapeutic interventions to reduce body weight and treat diabetes. Our more ‘basic’ research focuses on the control of substrate switching between fat and carbohydrate with a particular emphasis on the regulation of fatty acid oxidation in skeletal muscle and the adipose tissue dysfunction that occurs in obesity.
Insulin resistance in skeletal muscle is a key feature of the pre-diabetic state and a precursor to type 2 diabetes and cardiovascular diseases. Our laboratory developed several techniques to study substrate switching in primary human muscle cells and we use these techniques to better understand how insulin resistance develops. We also use these tools to develop and test new strategies to activate fat oxidation as a means to improve insulin action and reduce body weight. Myoblasts grown in culture retain the metabolic characteristics of the donor. This provides us with a tool to explore the origins of the reduced capacity for fat oxidation; a key feature of patients with type 2 diabetes and their offspring. Current efforts are directed towards identifying epigenetic ‘marks’ that may account for these intrinsic differences in the capacity for fat oxidation. Using these same tools, new data from the lab suggests that insulin resistance is due in part to dysregulation of the breakdown of lipid within the muscle; we coined the term intramyocellular lipotoxicity to describe the insulin resistance that occurs due to an imbalance in these lipases. These data suggest that intramyocellular DAGs lead to insulin resistance in humans, and the dysregulation of the key lipolytic enzymes ATGL and HSL lie upstream of insulin resistance in skeletal muscle. Lastly, we are aggressively pursuing the regulation of the NAD+ producing enzyme NAMPT in skeletal muscle which lies upstream of the SIRTs as a potential therapeutic pathway in diabetes.
Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.