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

One of the main functions of mitochondria, in addition to producing ATP, is to remove fatty acids by β-oxidation. In this way, mitochondria are able to remove NEFA and to protect the organism against fatty acid-induced insulin resistance and pancreatic beta cell lipotoxicity. β-Oxidation can take place in all cell types relevant for glucose homeostasis, including muscle, liver and adipocytes. During this process, fatty acids are oxidised in the mitochondrial matrix by NAD⁺ and flavin adenine dinucleotide (FAD), yielding acetyl coenzyme A, which is further degraded to CO₂ by the citric acid cycle. The resulting NADH and FADH₂ need to be recycled into NAD⁺ and FAD by the respiratory chain so that additional fatty acid molecules can be oxidised. This requires a supply of ADP, which is converted into ATP by respiratory chain activity. The rate of conversion of ATP back into ADP, which is determined by the metabolic activity of the cell, determines the rate at which fatty acids can be removed by mitochondrial activity. If the capacity of the cell to oxidise fatty acids is to be enhanced, ATP needs to be reconverted into ADP at an increased rate. This occurs during exercise in contracting muscle. The resulting enhanced rate of ADP generation provides a major additional sink for the oxidation of fatty acids within the body. Only when mitochondria are in the uncoupled state can regeneration of NAD⁺ and FAD occur without the conversion of ATP into ADP. The released energy is then converted into heat. Uncoupling is a physiological adaptation process, normally regulated by specific proteins [5]. It is remarkable that, like uncoupling proteins, fatty acids are capable of inducing mitochondrial uncoupling, especially when their concentrations exceed the binding capacity of fatty acid binding proteins [6‐8]. This implies that when unbound fatty acids are present in the cytosol of cells, mitochondria become less efficient at ATP production and generate more heat during the oxidation of NADH and FADH₂ derived from food.

White adipocytes contain large amounts of mitochondria in their tiny cytosolic compartment [9, 10]. There is no obvious reason why these cells need such a large capacity to produce ATP. We propose that, when uncoupled by fatty acids, these mitochondria prevent the release of fatty acids out of the adipocytes when the antilipolytic action of insulin is attenuated.

Evidence is accumulating that inflammation of adipose tissue is an early step in the pathogenesis of type 2 diabetes. The combination of excessive food intake with a sedentary lifestyle results in the formation of large adipocytes overloaded with triacylglycerols. Through as yet unknown mechanisms the adipose tissue becomes inflamed and infiltrated by leucocytes. This leads to the release of inflammatory cytokines such as TNF-α [11‐14], a potent inducer of insulin resistance in adipocytes which also induces lipolysis. As a result, fatty acids are released out of the large triacylglycerol pool [15]. We propose that, initially, a part of these fatty acids are removed inside adipocytes by partially uncoupled mitochondrial β-oxidation. In doing so, these mitochondria create a threshold for fatty acid release into the circulation, which would otherwise trigger the development of whole-body insulin resistance and pancreatic beta cell lipotoxicity, the latter expected to occur when the body cannot utilise these released fatty acids as fuel, for example, in response to high food intake and little physical exercise. Our proposed mechanism is outlined in Fig. 1. When low amounts of fatty acids are released out of the triacylglycerol pool in insulin-resistant adipocytes, these fatty acids can be removed by coupled β-oxidation. The rate of fatty acid removal by this pathway is determined by the rate of ADP regeneration within adipocytes, which is likely to be a more or less constant factor, merely determined by cellular metabolism and not affected by variations in the lipolytic rate. We propose that, when the rate of fatty acid release exceeds the rate of fatty acid removal by coupled β-oxidation, the increase in cytosolic concentrations of fatty acids not bound to binding proteins (unbound) induces a partial uncoupling of the mitochondria. Uncoupling by fatty acids has been shown in multiple in vitro experiments [5‐8, 16]. Evidence of uncoupling in vivo is provided by a study in which exposure of heart muscle to fatty acids resulted in a decrease in ATP production and a concomitant increase in oxygen consumption [17]. When uncoupled, the mitochondria are able to remove much larger quantities of fatty acids through generation of heat. The degree of uncoupling increases in with further elevations in fatty acid concentration, thus generating more heat. This represents a dynamic adaptation of the efficiency of the mitochondrion, which is determined by the intracellular concentration of fatty acids. If, however, the rate of fatty acid release exceeds the maximum clearance rate, fatty acids may reach concentrations that are toxic to the mitochondrion [18]. At this point β-oxidation capacity collapses and fatty acids are released out of adipocytes and redistributed over other tissues in the body. These ectopic triacylglycerol deposits are associated with the development of insulin resistance in muscle and liver and lipotoxicity in pancreatic beta cells [19]. At this stage of the disease process physical exercise will, by virtue of the generation of large amounts of ADP in muscle tissue, protect against lipotoxicity and the development of insulin resistance. This is because the muscle switches to β-oxidation to regenerate ATP when fatty acids reach a concentration sufficient to make the muscle resistant to insulin-stimulated glucose uptake [20, 21].