Mice lacking PKC-θ in skeletal muscle have reduced intramyocellular lipid accumulation and increased insulin responsiveness in skeletal muscle

Abstract

Protein kinase C-θ (PKC-θ) is a lipid-sensitive molecule associated with lipid-induced insulin resistance in skeletal muscle. Rodent models have not cohesively supported that PKC-θ impairs insulin responsiveness in skeletal muscle. The purpose of this study was to generate mice that lack PKC-θ in skeletal muscle and determine how lipid accumulation and insulin responsiveness are affected in that tissue. Mice lacking PKC-θ in skeletal muscle (SkM) and controls (SkM) were placed on a regular diet (RD) or high-fat diet (HFD) for 15 wk, followed by determination of food intake, fasting glucose levels, lipid accumulation, and insulin responsiveness. There were no differences between SkM and SkM mice on a RD. SkM mice on a HFD gained less weight from 10 through 15 wk of dietary intervention ( P < 0.05). This was likely due to less caloric consumption ( P = 0.0183) and fewer calories from fat ( P < 0.001) compared with SkM mice on a HFD. Intramyocellular lipid accumulation ( P < 0.0001), fatty acid binding protein 4, and TNF-α mRNA levels ( P < 0.05) were markedly reduced in SkM compared with SkM mice on a HFD. As a result, fasting hyperglycemia was mitigated and insulin responsiveness, as indicated by Akt phosphorylation, was maintained in SkM on a HFD. Liver lipid accumulation was not affected by genotype, suggesting the deletion of PKC-θ from skeletal muscle has a tissue-specific effect. PKC-θ is a regulator of lipid-induced insulin resistance in skeletal muscle. However, the effects of this mutation may be tissue specific. Further work is warranted to comprehensively evaluated whole body metabolic responses in this model.

[Retracted] Beta‐Sitosterol Facilitates GLUT4 Vesicle Fusion on the Plasma Membrane via the Activation of Rab/IRAP/Munc 18 Signaling Pathways in Diabetic Gastrocnemius Muscle of Adult Male Rats

“…In addition, diet-induced obesity disrupts glucose and lipid homeostasis, resulting in long-term impairment, dysfunction, and degradation of numerous tissues, particularly the pancreas, cardiovascular, skeletal muscle, and the blood vessels [ 32 , 33 ]. Chronic HFD intake effects in the storage of intramyocellular fat in the muscle, which is one of the primary sources of whole-body glucose clearance [ 34 , 35 ]. Extra intramyocellular lipid accumulation causes 5′ adenosine monophosphate-activated protein kinase inhibition, diacylglycerol and triacylglycerol aggregation, protein kinase C activity, and impaired glucose uptake, especially in sedentary populations [ 36 ].…”

Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review

“…Lack of PKCθ protects skeletal muscle from lipidinduced insulin resistance [152]. HFD-fed mice with skeletal muscle-specific PKCθ deficiency are characterized by decreased intracellular lipid accumulation and increased insulin sensitivity in skeletal muscle, decreased fasting glucose level, and lower daily calorie intake followed by lower weight gain in comparison to control mice [153]. Moreover, it was shown that activation of PKCθ induces inhibitory phosphorylation of IRSs at several residues, e.g.…”

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

“…PKCθ has been mostly studied in skeletal muscle, while PKCε has been predominantly investigated in the context of the insulin-resistant liver [ 8 ]. Recent work supported the role of nPKC by showing that muscle-specific PKCθ knockout mice were protected from high-fat diet (HFD)-induced IR [ 26 ]. The molecular mechanisms by which PKC disrupts insulin signalling have also been deeply investigated.…”