Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus

Abstract

Type 2 diabetes is associated with excessive food intake and a sedentary lifestyle. Local inflammation of white adipose tissue induces cytokine-mediated insulin resistance of adipocytes. This results in enhanced lipolysis within these cells. The fatty acids that are released into the cytosol can be removed by mitochondrial beta-oxidation. The flux through this pathway is normally limited by the rate of ADP supply, which in turn is determined by the metabolic activity of the adipocyte. It is expected that the latter does not adapt to an increased rate of lipolysis. We propose that elevated fatty acid concentrations in the cytosol of adipocytes induce mitochondrial uncoupling and thereby allow mitochondria to remove much larger amounts of fatty acids. By this, release of fatty acids out of adipocytes into the circulation is prevented. When the rate of fatty acid release into the cytosol exceeds the beta-oxidation capacity, cytosolic fatty acid concentrations increase and induce mitochondrial toxicity. This results in a decrease in beta-oxidation capacity and the entry of fatty acids into the circulation. Unless these released fatty acids are removed by mitochondrial oxidation in active muscles, these fatty acids result in ectopic triacylglycerol deposits, induction of insulin resistance, beta cell damage and diabetes. Thiazolidinediones improve mitochondrial function within adipocytes and may in this way alleviate the burden imposed by the excessive fat accumulation associated with the metabolic syndrome. Thus, the number and activity of mitochondria within adipocytes contribute to the threshold at which fatty acids are released into the circulation, leading to insulin resistance and type 2 diabetes.

Fig. 1

Consequences of fatty acid release from the adipocyte triacylglycerol pool. In insulin-sensitive adipocytes, fatty acid concentrations are kept low by insulin-induced antilipolytic action, re-esterification of fatty acids and mitochondrial β-oxidation. TNF-α induces insulin resistance and lipolysis. At low cytosolic concentrations of unbound fatty acids, the flux through mitochondrial β-oxidation is limited by the rate of ADP generation by cellular metabolism. At intermediate concentrations of unbound fatty acids, uncoupling of mitochondria is induced leading to continuous oxidation of fatty acids, independent of ADP supply. This process generates heat and keeps cytosolic fatty acid concentrations low. When the rate of fatty acid release from the triacylglycerol pool exceeds the rate of fatty acid removal, high cytosolic concentrations of unbound fatty acids develop, which induce mitochondrial damage [18]. This results in a decline in the capacity to remove fatty acids and the release of large amounts of fatty acids into the circulation. Unless these are removed by muscle activity they form ectopic triacylglycerol deposits and induce whole-body insulin resistance and beta cell damage. Dotted arrows indicate consequences; continuous arrows, fluxes

Fig. 2

Proposed sequence of events leading to the development of hyperglycaemia during the metabolic syndrome. When adipocytes become overloaded with triacylglycerol, low-grade inflammation develops and inflammatory cytokines such as TNF-α induce insulin resistance in the adipocytes. This results in an elevated state of lipolysis. When fatty acids are inadequately removed within adipocytes because of mitochondrial dysfunction (for example, induced by fatty acids or HAART therapy, fatty acids appear in the circulation, where they induce insulin resistance of muscle and liver and malfunction of pancreatic beta cells. The elevated circulating fatty acid concentrations may also uncouple mitochondria in artery wall smooth muscle cells, thereby elevating the risk of hypertension [46]. Thiazolidinediones (TZDs) ameliorate the disease process in two ways: (1) by creating more mitochondria in adipose cells [23, 36, 37], thereby enhancing the capacity for oxidation of fatty acids; and (2) by enhanced re-esterification of fatty acids [39, 40]