The Beneficial Effects of Brown Fat Transplantation: Further Evidence of an Endocrine Role of Brown Adipose Tissue.

Abstract

Transplantation procedures have been traditionally used in endocrinology research to assess the ability of factors secreted by transplanted tissues and organs to signal at distance to other tissues and organs. This strategy contributed to reveal the role of white adipose tissue (WAT) as an endocrine organ. For example, studies showing that white fat transplantation caused the systemic amelioration of metabolism in lipoatrophic mice contributed significantly to current awareness that white fat, in addition to its role as a site of storage of metabolic energy, is an active site of release of bioactive molecules with hormonal action, known as adipokines (1). Brown adipose tissue (BAT) is a form of adipose tissue completely distinct from WAT. Rather than being a site of lipid storage, BAT is the main site of nonshivering thermogenesis. The uncoupled oxidation occurring in mitochondria of BAT results in the consumption of metabolic substrates and the production of heat. Studies in rodents have shown that activation of BAT has healthy metabolic consequences in regard to obesity and type 2 diabetes. Promotion of energy expenditure by brown fat protects against obesity by preventing a potentially positive energy balance (2). Moreover, the ability of brown fat to actively drain circulating glucose and triglycerides, oxidizing them to produce heat, can prevent hyperglycemia and hypertriglyceridemia (3). In humans, BAT was previously thought to play a relevant role only in neonatal thermogenesis. However, the recent findings that adult humans have higher amounts of active brown fat than expected has renewed interest in the role of brown fat activation in promoting metabolic health (4). In the last years, several reports using rodent models have indicated that transplantation of BAT has beneficial effects on metabolic health. For example, transplantation of embryonic BAT into rodent models of type1 diabetes, induced by streptozotocin or associated with autoimmune processes (5, 6), was found to normalize glycemia. These effects were independent of insulin, which remained abnormally low after transplantation, and were accompanied by increased amounts of sc white fat and reduced signs of WAT inflammation. The beneficial effects of BAT transplantation were proposed to be due to significant increases of adipokines, such as adiponectin and leptin, originating from the newly replenished sc WAT. IGF-1, released by transplanted BAT, has been proposed to play a major role in improving type 1 diabetes in this experimental model. In 2013, 2 independent laboratories (7, 8) reported that adult BAT transplantation could reverse metabolic abnormalities in high-fat diet-induced obese, insulin-resistant, mice. In one study, BAT transplantation improved glucose tolerance, increased insulin sensitivity, reduced body weight, and completely reversed high-fat diet-induced insulin resistance (7). The other study found that BAT transplantation could prevent and even reverse high-fat dietinduced obesity in mice (8). Although one study has found that the main targets of BAT transplantation were the WAT and BAT of transplant recipients, the other study reported that transplanted BAT primarily activated BAT and muscle. However, despite some discrepancies in the processes underlying the effects of transplanted BAT and several technical differences (eg, the site of transplantation