Beyond erythropoiesis: emerging metabolic roles of erythropoietin.

Infiltration of inflammatory cells into adipose tissue causes insulin resistance in animal models and is associated with insulin resistance in humans (1,2). Among potential therapeutic approaches, the hormone erythropoietin (EPO) exerts anti-inflammatory effects in a variety of nonerythroid tissues (3), in which the receptor for EPO (EPO-R) is widely expressed (4). Various observations suggest a relationship between EPO and diabetes. There is an increased prevalence of anemia with inadequate EPO response in diabetes (5), and treatment of anemia slows the progression of microvascular and macrovascular complications (6). EPO reduced glucose levels in nondiabetic humans (7) and reduced diet-induced obesity and suppressed gluconeogenesis in rodents (8,9). While EPO increases adipose tissue oxidative metabolism and deletion of EPO in adipocytes results in obesity (10), failure to reproduce this highlights potential genetic and environmental influences (11). EPO has cytoprotective, proliferative, and anti-inflammatory effects in a variety of tissues including pancreatic β-cells, protecting against experimental models of both type 1 and type 2 diabetes (12,13).

In this issue, Alnaeeli et al. (14) elegantly demonstrate a pharmacologic role of EPO in attenuating adipose tissue inflammation prior to changes in body weight. The authors show that EPO-R is disproportionately highly expressed in adipocytes and adipose inflammatory cells, and both pharmacologic and endogenous EPO promote the skewing of adipose macrophages to an alternatively activated, predominantly M2 state. Beneficial roles of EPO are not only abolished when EPO is given to mice lacking EPO-R except in erythroid cells, but these EPO-R−deficient mice have an unopposed proinflammatory phenotype with predominance of M1-activated macrophages. Thus, the predominance of anti-inflammatory M2 macrophages in the lean nondiabetic state may be at least in part restrained by endogenous EPO. As M2 macrophages play an important role in tissue growth and differentiation, beneficial effects of EPO in tissue injury may be achieved through effects on macrophages in addition to a direct cytoprotective role.

While Alnaeeli et al. attributed EPO’s metabolic benefit to effects on adipose tissue macrophages, their finding that EPO expression is high in stromal vascular fraction cells suggests that EPO might exert its effects via other inflammatory cells, which in turn could impact the inflammatory status of adipose macrophages (15). As EPO’s effects on glucose tolerance and inflammation were more striking than on insulin sensitivity, these effects may represent an association rather than a causal relationship. Indeed, some of the observed metabolic effects may be attributable to EPO’s effects on β-cells (12). Could there be an additional role for the brain in mediating EPO’s effects? EPO-R is abundantly expressed in hypothalamic proopiomelanocortin (POMC) neurons (16), and glucose sensing by POMC neurons contributes to regulation of systemic glucose metabolism (17). Another intriguing question is whether some of the insulin-sensitizing effects might be mediated by EPO-induced decreases in systemic iron stores (18), given the known association between iron overload and insulin resistance (19) (Fig. 1).

Figure 1

Erythroid and nonerythroid effects of EPO. Under hypoxic conditions, EPO promotes increased production of red blood cells (RBC). In the hypothalamus, EPO-Rs expressed in POMC-producing neurons regulate food intake and energy expenditure. In white adipose tissue, EPO decreases inflammation, normalizing insulin sensitivity and reducing glucose intolerance. In the pancreas, EPO exerts anti-apoptotic, anti-inflammatory, proliferative, and angiogenic effects on β-cells.

The study by Alnaeeli et al. (14) provides novel insights into both pharmacologic and endogenous roles of EPO that improve glucose tolerance and reduce inflammation. Thus, EPO’s extra-erythropoietic actions may offer novel approaches to diabetes prevention and treatment. As increased risk of thrombogenesis and hypertension (4) suggest that EPO be used cautiously in diabetes, selectively harnessing EPO’s favorable metabolic effects may have therapeutic potential (20).