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

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 diet-induced 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 and the ages of the donors and recipients), the effects in both studies were remarkably similar. The interpretation of these studies is that transplanted BAT results in systemic signaling that targets the recipient's tissues but is relatively uninvolved in overall energy balance, as shown by the small amounts of transplanted BAT and evidences showing that the metabolic oxidative activity of transplanted BAT tends to decline with time. Attempts to identify the signals arising from transplanted BAT have disclosed that BAT transplanted from IL-6-null mice did not have the healthy metabolic effects of wild-type BAT (7). Although this finding may suggest the importance of IL-6 in mediating the systemic effects of transplanted BAT, the scenario appears rather complex, as one of the main outcomes of wild-type BAT transplantation was an increase in fibroblast growth factor-21 (FGF21) levels, an increase not observed after transplantation of BAT from IL-6-null mice (7). IL-6 and FGF21 are among the better-known BAT adipokines, being induced and released by BAT in response to noradrenergic mediated pathways (9, 10). IL-6 is usually considered a proinflammatory cytokine, with effects that are poorly compatible with improved insulin sensitivity. However, this view of the role of IL-6 role on metabolism has been brought in to question, especially given recent findings showing that IL-6 is also a myokine released by skeletal muscle during exercise (11) and promotes pancreatic insulin secretion (12). For FGF21 the scenario would appear at first glance to be even more consistent: FGF21 is an endocrine factor released by BAT under conditions of thermogenic activation (10), having effects favoring glucose homeostasis, reducing hyperlipidemia and even preventing obesity (13) and targeting BAT activity (14). Thus, IL-6 and most likely FGF21 appeared to be BAT-secreted factors that mediate the healthy metabolic effects of transplanted BAT. In the present issue of Endocrinology, Liu et al (15) present further evidence of a potential endocrine role of BAT by reporting the action of BAT transplantation in a genetic model of obesity, the leptin-deficient ob/ob mouse. Liu et al found that, in this model, BAT transplantation reduced body weight and increased energy expenditure without affecting food intake. As in previous reports, grafted BAT showed a progressive tendency to involute but enhanced endogenous BAT activity. Transplanted BAT amelioration of the metabolic profile of ob/ob mice included improved glucose tolerance and reduced hepatic steatosis. Despite suggestions that FGF21 may mediate the actions of transplanted BAT (as both BAT-born adipokine and positive effector of BAT thermogenic activity), FGF21 levels were significantly reduced after BAT transplantation. Similarly, alterations in IL-6 levels could not account for the observed changes. Rather, only an increase in adiponectin could account for the systemic beneficial effects of BAT transplantation. Surprisingly, however, neither transplanted BAT, nor recipients' BAT and sc WAT showed enhanced expression of adiponectin. Moreover, this study showed for the first time that an unaltered leptin system is not required for the metabolic effects of transplanted BAT. In summary, BAT transplantation studies, such as those of Liu et al (15), are confirming the ability of BAT to elicit signals that positively influence metabolism, avoid or attenuate the alterations associated with high-fat diet or genetically induced obesity, and, in some instances, even prevent obesity itself. Moreover, these studies have shown that systemic effects of BAT activation do not require large amounts of active BAT. However, they also highlight our relative lack of knowledge of the BAT secretome and the identity of the main bioactive agents produced by BAT and accounting for the beneficial metabolic effects of BAT activation (16). In this sense, the role of recently identified signaling molecules originating from BAT such as bone morphogenetic protein-8b (17) and neuregulin-4 (18), in the metabolic outcome of BAT transplantation procedures should deserve further attention. The biomedical potential for metabolic therapy suggested by BAT transplantation studies requires the precise identification of the BAT-secreted molecules, which might pave the way for novel pharmacological tools that influence metabolic health. Admittedly, the potential of BAT transplantation (or cell-based transplantation of human brown adipocytes) to treat metabolic alterations in humans, as discussed previously (19), is still hypothetical. Nonetheless, the availability of surgical procedures for fat transplantation in humans, with reconstructive or esthetic purposes, might provide the technical basis for future developments in fat transplantation for metabolic therapy. In summary, although it may appear surprising that research conducted in recent years, well after the beginning of the 21st century, has led to the recognition of a new “endocrine” organ, findings on the signaling capabilities of BAT, as shown by the study published in this issue of Endocrinology by Liu et al, unambiguously document that BAT is a source of secreted molecules that can affect metabolism. Additional research is therefore warranted to define the molecular identity of these BAT-born signals. This work was supported by the Ministerio de Ciencia e Innovación Grant SAF2014–55725 and by the Instituto de Salud Carlos III, Spain Grant PI14/00063. Disclosure Summary: The authors have nothing to disclose. brown adipose tissue fibroblast growth factor-21 white adipose tissue.