Attempts to address the public health risk of obesity are focusing on brown and beige adipose tissue, which are promising therapeutic targets for combating human obesity and related metabolic disorders. Brown and beige adipocytes become metabolically activated in response to cold-stimulated release of norepinephrine by the sympathetic nervous system, where they expend energy stored in glucose and lipids to generate heat. This process, known as non-shivering thermogenesis, likely evolved in mammals to increase neonatal survival and provide warmth in cold temperatures. Studies in mice show that activated brown adipose tissue can prevent obesity through increased energy expenditure and protect against diet-induced insulin resistance and hepatic steatosis (fatty liver) through paracrine/endocrine signaling. Modifying obesity and diabetes in humans by stimulating energy expenditure in adipose tissue with drugs has largely been unsuccessful. One potential alternative to drugs is to generate cell-based therapies to supplement obese patients with additional brown or beige adipose tissue, their adipogenic precursors, or secreted factors derived from these cells. However, in humans, brown and beige adipocyte progenitor cells require invasive methods to procure, and have restricted expansion and differentiation potential and become more limited or absent with increasing age and weight gain. To overcome these problems, our laboratory has developed human models of brown and beige adipocytes by reprogramming somatic cells from diabetic patients using induced pluripotent stem cell (iPSC) technology. These iPSC-derived adipocytes are renewable, show high metabolic activity and secrete anti-diabetic factors, making them a good model for generation of anti-obesity/diabetic therapies. We are currently generating 3-dimensional adipose tissue models for engraftment testing in obese/diabetic mice to determine their overall regenerative potential. In addition, we are studying factors secreted by thermogenic adipocytes that may have the potential reverse metabolic dysfunction.

Above: Immunohistochemistry image showing large lobules of multilocular, UCP1 positive beige fat cells (brown colored stain, bottom half of tissue section) forming in subcutaneous adipose tissue after mice are exposed to colder temperatures. These beige fat cells contain specialized mitochondria that burn energy and can be distinguished from the larger, unilocular white adipocytes that store energy (white colored with blue hematoxylin counterstain, top half of the tissue section). Formation of beige fat cells during cold exposure is associated with resistance to obesity and type 2 diabetes.