Molecular Circuits Controlling Brown Adipose Tissue (brown fat) Formation
Obesity is a leading preventable cause of death worldwide. Defined as a pathological accumulation of body fat and generally resulting from a long-term positive energy balance (intake exceeds expenditure), obesity has a number of complications and co-morbidities such type-2 diabetes, cardiovascular disease, stroke and cancer.
Brown adipose tissue (BAT) is an energy-dispensing thermogenic tissue that plays an important role in balancing energy metabolism. As little as 50g of brown adipose tissue,
less than 0.1% of adult human body weight, can utilize up to 20% of basal caloric needs if maximally stimulated. However, active BAT is very scarce in adult human, particularly in obese people. Thus, stimulating an increase in the amount of energy-expending BAT will provide a defense against, and potential treatment for, obesity.
We recently discovered that adult muscle stem cells (also called satellite cells) are multipotent and give rise to brown adipocytes (the functional component of BAT) as well as muscle progenitors. We found the lineage choice between myogenic and brown adipose determination is controlled by a non-coding RNA (microRNA-133; see diagram on left). Strikingly, antagonism of microRNA-133 with a chemically-engineered antisense oligonucleotide (ASO) during muscle regeneration resulted in increased uncoupled respiration, glucose uptake and thermogenesis in local treated muscle, which led to long-term augmentation of whole-body energy expenditure, protection from obesity and improved glucose tolerance.