Simply put…

Despite the clinical focus on increasing fatty acid oxidation to clear surplus fat stores in obese and diabetic individuals, new research suggests that increasing fatty acid metabolism does more harm than good. This article provides insight into the complex balance of glucose and fatty acid metabolism, and why blocking fatty acid metabolism may be a more appropriate therapeutic option for obese and type 2 diabetic patients.

The link between obesity and diabetes is unquestionable, so the global rise in obesity and type 2 diabetes (T2D) rates is no surprise. A 2014 report from Statistics Canada suggests that more than five million Canadian adults are obese, out of which more than three million were diagnosed with T2D. In 2010, diabetes and pre-diabetes cost the Canadian health care system over two billion dollars. With all these numbers expected to double in the next decade, there is a glaring need for interventions to slow down this North American epidemic.

T2D is a chronic disease where insulin, a hormone that controls blood glucose levels, can no longer stimulate body tissues to utilize glucose for energy. The direct result of this insulin resistance is elevated glucose, which is lethal to nerves, blood vessels, and numerous tissues including liver, skeletal muscle, pancreas, heart and adipose tissue. Patients with diabetes have elevated levels of blood glucose, insulin, and free fatty acids. The increase in free fatty acids is of particular interest, as free fatty acids can stimulate glucose production in the liver (gluconeogenesis) further perpetuating the disease (1). Normally, a well-established balance exists between utilizing glucose and fat as fuels. In the fasted state, fat metabolism is increased, which decreases glucose oxidation and increases gluconeogenesis, thus preserving blood glucose for use by the brain. Conversely, fatty acid oxidation is decreased in the fed state, which increases glucose oxidation and decreases gluconeogenesis (2).

This transition from fatty acid to glucose oxidation from the fasted to fed state is heavily impaired in obese and diabetic patients where all metabolically active tissue types are locked in an inflexible fatty acid dependent state (3) (see Figure 1). Despite this finding, the clinical focus for many decades has been increasing fatty acid oxidation to clear surplus fat stores in obese and diabetic individuals, as an intuitive approach to improve insulin sensitivity. This article aims to discuss how blocking fatty acid oxidation in the context of inactivity, over-nutrition, obesity, and diabetes may be an established, alternative therapeutic strategy. In other words, burning less fat may be better!

A simple recap on how our cells breakdown glucose and fat for energy (ATP), makes this concept easier to grasp (see Figure 2). Glucose metabolism involves three key steps: glycolysis, Krebs cycle and oxidative phosphorylation. First, glycolysis involves the enzymatic conversion of glucose to pyruvate in the cytosol, after which pyruvate enters the mitochondria to take part in the Krebs cycle. Once in the mitochondria, pyruvate is converted to acetyl-CoA and then citric acid, which goes through eight enzymatic rearrangements to create Krebs cycle intermediates (keto acids) as well as reducing equivalents (NADH and FADH2). The reducing equivalents from the Krebs cycle are used in oxidative phosphorylation where a series of redox reactions occur in the inner mitochondrial membrane producing an electrochemical gradient that generates ATP. Fatty acids, on the other hand, must be esterified to fatty acyl-CoA prior to oxidative degradation in the mitochondrial matrix via the fatty acid-oxidation pathway. Fatty acyl-CoA uptake into mitochondrial matrix is dependent on the conversion of fatty acyl-CoA to fatty acyl-carnitine by carnitine palmitoyltransferase-1 (CPT-1), which is the rate limiting enzyme for fatty acid uptake (2). The beta-oxidation pathway is initiated upon entry of the fatty acids into the mitochondrial matrix in an appropriate form. Much like how pyruvate from glucose is converted to acetyl-CoA to be used by the mitochondria, each long chain fatty acyl-CoA molecule has two carbons removed every oxidation cycle to yield acetyl-CoA and the reducing equivalents, which take part in the Krebs cycle and oxidative phosphorylation to produce energy (ATP).

Having reviewed how glucose and lipids both have to use the Krebs cycle and oxidative phosphorylation to be completely metabolized, one should appreciate how important it is for the mitochondria to shift from lipid metabolism during the fasted state and to glucose metabolism during the fed state, a process termed the Randle cycle (2). The dietary lipid surplus and low physical activity status in obese individuals usually precedes the onset of diabetes, as excessive fatty acids get converted into fatty acyl-CoAs and accumulate in the mitochondria causing overload (4). Mitochondria overloaded with fatty acyl-CoA begin to undergo excessive βoxidation that i) immediately shuts down glycolysis (and thus glucose utilization) (2), ii) causes incomplete oxidation of fatty acids as mitochondrial control is lost (4) and iii) depletes several substrates and intermediates of the Krebs cycle, impeding oxidative phosphorylation for ATP production (4). All of these events play a significant role in causing weight gain, insulin resistance, and T2D for two reasons. First, the excessive fatty acid oxidation reduces glucose metabolism and chronically raises blood sugar, which impairs glucose stimulated insulin secretion and depletes insulin stores in pancreatic beta-cells as they try to compensate (5, 6). Second, the incomplete oxidation of fatty acids leaves behind un-metabolized fatty acyl-CoAs and other intermediates that further deplete pancreatic beta-cell insulin stores and also produce harmful reactive oxygen species (7). Many of these observations have been made in skeletal muscles of rodents and humans; skeletal muscles account for more than 70% of all glucose utilization in the body (2, 8). For these reasons, inhibiting fatty acid oxidation in skeletal muscle is a therapeutic strategy to improve whole-body insulin sensitivity and glucose tolerance in obese and diabetic individuals.

Research to date comprehensively points to blocking fatty acid oxidation as an established therapeutic approach for the treatment of T2D. In animal models of obesity and diabetes, CPT-1 inhibitors (e.g. etomoxir and oxfenecine) were lead candidates for clinical development as they i) improved glucose utilization by causing a shift towards the more thermogenic oxidative phosphorylation and glycolysis (1, 9), ii) reduced hyperglycemia via inhibiting liver gluconeogenesis and improving glucose homeostasis (10, 11), and iii) increased the expression of mitochondrial uncoupling proteins, which protect against oxidative stress and boost glucose stimulated insulin secretion (12). Despite the pre-clinical promise of CPT-1 inhibitors, human clinical trials on etomoxir revealed adverse cardiovascular and hepatic toxicity as the high effective clinical dose was impeding mitochondrial function in muscle, liver and heart tissue (13, 14).

CPT-1 inhibitors are certainly not the only avenue for achieving fatty acid oxidation inhibition in obese and diabetic individuals. Fatty acid oxidation inhibition can be achieved more downstream of fatty acid uptake into mitochondria; for instance, certain enzymes of beta-oxidation can be inhibited. Additionally, a glucose-derived metabolite, malonyl-CoA, is known to block fatty acid oxidation as part of the Randle cycle. As such, boosting levels of malonyl-CoA has also been found, though only pre-clinically, to decrease insulin resistance (15). The clinical dose limiting toxicity of synthetic fatty acid oxidation inhibitors like etomoxir does not place questions over the science behind this therapeutic strategy. Rather, it highlights the need for a natural bioactive that can be developed as a fatty acid oxidation inhibitor for metabolic diseases.

References

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