Diabetes mellitus is a disease defined by elevated blood glucose levels. The causes of type 2 diabetes are not well understood. It is thought that both resistance of target tissues to the action of insulin and decreased insulin secretion (“β-cell failure”) occur. Major insulin-responsive tissues for glucose homeostasis are liver, in which insulin stimulates glycogen synthesis and inhibits gluconeogenesis; muscle, in which insulin stimulates glucose uptake and glycogen synthesis; and white adipose tissue (WAT), in which insulin stimulates glucose uptake and inhibits lipolysis. The relative importance of each tissue is not known; nor are the details of how they interact.
To understand the physiological roles of adipose tissue, we have generated a transgenic line of mice, named A-ZIP/F-1, which has virtually no white adipose tissue (1
). These mice express a dominant negative protein in adipose tissue that heterodimerizes with and inactivates members of the C/EBP and JUN families of B-ZIP transcription factors. The A-ZIP/F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes, including the lack of fat, marked insulin resistance and hyperglycemia, hyperlipidemia, fatty liver, and organomegaly. The detailed mechanisms by which the lack of WAT causes insulin resistance are not established. Contributing components probably include deficiency of leptin (and other hormones) and the lack of a place to store triglycerides (2
). It has been postulated that increased intracellular triglycerides (or metabolites such as fatty acyl-CoA or malonyl-CoA) inside nonadipose tissues could cause insulin resistance (6
The TZDs are a class of antidiabetic agents that act by increasing insulin sensitivity (8
). Currently, two drugs in this class are approved for use in the United States, rosiglitazone (formerly BRL49653; ref. 10
) and pioglitazone. TZDs are agonist ligands for the transcription factor peroxisome proliferator-activated receptor γ (PPARγ), and their antidiabetic effects are thought to be mediated through PPARγ (11
). PPARγ is expressed at high levels in adipose tissue, colon, and activated macrophages, and at lower levels in other tissues (12
). The tissues at which TZDs act to increase insulin sensitivity are debated (8
). TZDs increase glucose utilization (largely a muscle function) and, at higher doses, inhibit endogenous glucose production (largely a liver function) (19
). However, liver and muscle have low PPARγ levels. Thus, WAT has been a leading candidate for the target of TZD actions, as it is the only insulin-responsive tissue with a high level of PPARγ. Additionally, PPARγ and its agonist ligands stimulate adipose differentiation (20
), leading to increased numbers of small adipocytes, which are thought to be more insulin sensitive than are large, lipid-laden adipocytes (21
). However, Burant et al., studying a partially lipoatrophic mouse, concluded that troglitazone effectively treated diabetes, independent of adipose tissue (22
). Here, we have reexamined this question using the more severely lipoatrophic A-ZIP/F-1 mice and do not see an effect of TZDs on insulin and glucose levels. However, rosiglitazone greatly increases the hepatic steatosis of these mice, which may be due to their increased hepatic expression of PPARγ.