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The Quest To Make Visceral Fat Burn Itself

Seeking to learn what sparks the appearance of calorie-burning “brown fat” cells within the body’s visceral fat tissue, researchers have identified their origins, or progenitor cells, in mice, and molecular regulators in both mouse and human tissue that may lead to new therapeutic strategies for obesity and related diseases. Humans and mice harbor different types of fat tissue. Calorie-storing “white fat” tissue is the most abundant, and can be found surrounding internal organs, where it is referred to as visceral or abdominal fat, and just under the skin, a location termed subcutaneous. Brown fat, which burns calories to generate heat, also takes various forms, but is more transient. Babies and rodents have brown fat tissue that, in the case of humans, largely disappears after infancy. However, cells with characteristics of brown fat (sometimes called beige or brite cells) can also appear within patches of white fat tissue, in response to cold or other nervous-system triggers. Typical brown fat tissue develops from progenitor cells that are related to another calorie-burning tissue, muscle, but the origin of brown fat cells that arise within white fat tissue has been unknown. Based on previous reports that suggested a protein called PDGFRα might mark such progenitor cells, scientists tagged visceral fat cells in mice in a way that would mark not only progenitor cells with this protein, but also all cells descending from them. Subsequently, they put some of the mice on a high-fat diet for 8 weeks, and gave the other mice a chemical that stimulates factors in the nervous system (β3-adrenergic receptors) to cause heat generation. Examining the tagged cells, the researchers found that after β3-adrenergic stimulation, the progenitors gave rise to new cells with characteristics of brown fat. By contrast, the high-fat diet led to new white fat cells. Having illuminated two divergent paths for visceral fat progenitor cells, scientists may develop therapies that steer these cells toward brown fat development. 
 
In other recent studies, scientists explored ways to remove molecular barriers to brown fat development within visceral white fat tissue. One team focused on a protein called ActRIIB, which limits muscle mass and regulates fat tissue. Building on previous research, they developed a “decoy” version, ActRIIB-Fc, to subvert the effects of the normal protein, and administered it to mice along with a high-fat diet. Compared with mice that did not receive the decoy, those that did had increased lean tissue (muscle) mass and less fat tissue; they were protected from metabolic effects of a high-fat diet, such as abnormal fat accumulation in the liver; and within their visceral fat were cells that had activated genes characteristic of brown fat. While this study shows that ActRIIB-Fc can prevent diet-induced obesity, future research may determine whether it could help treat mice that are already obese, and whether this approach may work in people. Pursuing an alternate route from white to brown fat, another research team investigated a molecule called retinaldehyde, which is related to vitamin A and is found in white fat, along with an enzyme that processes it, called Aldh1a1. The researchers observed the enzyme in visceral white fat, with higher levels observed in mice fed a high-fat diet and in people who were extremely obese. A chemical inhibitor of this enzyme, when injected into obese mice, limited further weight gain from a high-fat diet; improved their glucose levels, a sign of reduced diabetes risk; and activated brown fat genes in visceral fat tissue.

By revealing previously unknown brown fat progenitor cells and exploring factors that regulate brown fat development, these and other studies may lead to new obesity therapies that coax cells in visceral white fat tissue to burn calories like brown fat.

Kiefer FW, Vernochet C, O’Brien P, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med 18: 918-925, 2012.

Koncarevic A, Kajimura S, Cornwall-Brady M, et al. A novel therapeutic approach to treating obesity through modulation of TGFβ signaling. Endocrinology 153: 3133-3146, 2012.

Lee YH, Petkova AP, Mottillo EP, and Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab 15: 480-491, 2012.