Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Abstract

The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

“…This affects also intracellular acyl-CoA content which accumulates in skeletal muscle due to inhibition of sphingolipid biosynthesis. Analogous mechanisms were observed in plasma and skeletal muscle of CD36 [33] or CPT1b knock-out mice [34] where blocking of FA uptake to skeletal muscle or mitochondria led to plasma FA and intramuscular lipids accumulation. In the same way PGC-1α protein ablation leads to intracellular TAG accumulation in L6 myotubes due to impaired mitochondrial FA metabolism [35].…”

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

“…Animal Procedures and Serum Analyses-For studies on OSMR FKO mice and controls, non-fasting body composition was analyzed by NMR (Bruker LF50, Bruker Optics, Germany) at baseline and every other week for the duration of the study (51,52). Body weights were obtained weekly.…”

“…injections of 20% dextrose. Tail glucose was measured at baseline (time 0) prior to the administration of insulin or glucose and at the indicated postinjection time points as described previously (51,52). At study end, blood was collected via cardiac puncture, centrifuged at 3500 rpm for 15 min at 4°C, and serum was removed and stored at Ϫ80°C until analyzed.…”

Impaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle

“…Carnitine palmitoyltransferase-1 (CPT1) is located on the outer mitochondrial membrane and transports long-chain fatty acids into mitochondria for β-oxidation. We created a mouse model of impaired fatty acid oxidation (FAO) by deleting carnitine palmitoyltransferase-1b in skeletal muscle ( Cpt1b m−/− ) and reported that inhibition of mitochondrial FAO leads to activation of AMPK and PGC1α, resulting in adaptive metabolic responses in skeletal muscle with increased mitochondrial biogenesis, oxidative capacity, compensatory peroxisomal fat oxidation and amino acid catabolism (Wicks et al, 2015). In addition, despite elevated plasma lipids, and accumulation of both intramyocellular lipids (IMCL) and lipotoxic species, fasting insulin and glucose are lower in Cpt1b m−/− mice with enhanced glucose utilization in Cpt1b m−/− mice.…”