Intramyocellular lipid kinetics and insulin resistance

Abstract

More than fifteen years ago it was discovered that intramyocellular triglyceride (imcTG) content in skeletal muscle is abnormally high in conditions of lipid oversupply (e.g. high fat feeding) and, later, obesity, type 2 diabetes (T2D) and other metabolic conditions. This imcTG excess is robustly associated with muscle insulin resistance (MIR). However, to date the pathways responsible for the imcTG excess and the mechanisms underlying the imcTG-MIR correlation remain unclear. A current hypothesis is based on a backward mechanism that impaired fatty acid oxidation by skeletal muscle causes imcTG to accumulate. As such, imcTG excess is considered a marker but not a player in MIR. However, recent results from kinetic studies indicated that imcTG pool in high fat-induced obesity (HFO) model is kinetically dynamic. On one hand, imcTG synthesis is accelerated and contributes to imcTG accumulation. On the other, the turnover of imcTG is also accelerated. A hyperdynamic imcTG pool can impose dual adverse effects on glucose metabolism in skeletal muscle. It increases the release and thus the availability of fatty acids in myocytes that may promote fatty acid oxidation and suppress glucose utilization. Meanwhile, it releases abundant fatty acid products (e.g. diacylglycerol, ceramides) that impair insulin actions via signal transduction, thereby causing MIR. Thus, intramyocellular fatty acids and their products released from imcTG appear to function as a link to MIR. Accordingly, a forward mechanism is proposed that explains the imcTG-MIR correlation.

Figure 1

Hydrolysis of imcTG produces DAG and LCACoA which is also precursor to ceramides. All three can activate PKC isoforms that inhibit insulin signaling. An enlarged and rapidly turning over imcTG pool increases the release of these fatty acid derivatives, thus causing MIR. Simultaneously, mitochondrial β-oxidation may increase given the large fatty acid flux thereby worsening MIR. FFA, (plasma) free fatty acids; LCFA, long chain fatty acids; LCACoA, long chain acyl CoA; LCAC, long chain acylcarnitines; PL, phospholipids; DAG, diacylglycerol; PKC, protein kinase C; β, mitochondrial β-oxidation.

Figure 2

Schematic representation of forward (solid arrows) and backward (broken arrows) mechanism underlying MIR, as discussed. By the forward mechanism, imcTG is at a hyperdynamic state characterized by accelerated synthesis (Syn, ref. 21) and turnover (TO, ref. 31) in the earlier stages of metabolic complications such as obesity. This increases the flux and availability of intramyocellular fatty acids (FA/LCFA), DAG, LCACoA and ceramides and thus signaling via PKC system, and promotes mitochondrial β-oxidation (β). As a result, PI3K is inhibited and GLUT4 translocation impaired resulting in reduced insulin-mediated glucose uptake (MIR). Over time, the overloading of mitochondria by β-oxidation gradually causes mitochondrial damages and dysfunctions (MD) via mechanisms such as oxidative stress and DNA damage. When this occurs, mitochondrial β-oxidation reduces. At this stage (e.g. T2D or advanced aging), the backward mechanism prevails. The decline in fatty acid oxidation causes imcTG to accumulate. Gray-scaled mitochondria (mito) represents damaged mitochondria. The thickness of arrows approximates the sizes of the fluxes.