The Role of PGC-1α in the Development of Insulin Resistance in Skeletal Muscle - Revisited

Abstract

Currently, obesity is a predominant medical condition and an important risk factor for the development of several diseases, including type 2 diabetes mellitus. Importantly, most research has indicated lipid-induced insulin resistance in skeletal muscles is a key link between the aforementioned pathological conditions. PGC-1α is a prominent regulator of myocellular energy metabolism orchestrating gene transcription programming in response to numerous environmental stimuli. Moreover, it is widely acknowledged that mitochondrial metabolism (primary metabolic target of PGC-1α) disturbances are widely acknowledged contributors to type 2 diabetes development. Therefore, it seems surprising that the exact physiological contribution of PGC-1α in the development of insulin resistance in skeletal muscle remains poorly understood. This review aims to reconcile these allegedly different findings by looking for a common denominator in the role(s) of PGC-1α in respect to lipid-induced insulin resistance in skeletal muscle. Our scrutiny of the literature indicates that interventions at the level of PGC-1α may exert beneficial effects on myocytes in respect to lipid-induced insulin resistance. The latter takes place as a result of a positive net energy balance (fatty acids oxidation surpassing their accumulation rate). Moreover, the aforementioned effects may not necessarily be limited to physically active states. They seem to occur, however, only within a physiologically observed range in muscle cells (approximately 1-fold changes in PGC-1α protein expression).

Insulin Resistance and Obesity Affect Lipid Profile in the Salivary Glands

“…At first glance, this novel and intriguing finding seems to be quite unexpected. Many authors point on the causative relationship between DAG over accumulation and insulin resistance in peripheral tissues (e.g., skeletal muscles, adipose tissue, and liver) [ 2 , 4 ]. However, we should be aware that the salivary glands are not as vitally involved in the development of this metabolic condition as the aforementioned tissues (due to their relatively large mass and high metabolic activity) are.…”

“…More specifically, a lot of research indicates that lipids are vitally involved in the onset of a peripheral tissue (e.g., skeletal muscle, heart, liver, and adipose tissue) insulin resistance [ 1 – 3 ]. The latter seems to occur in relation to an imbalance between superfluous cellular free fatty acids (FFAs) supply and their inadequate utilization in the process of mitochondrial β -oxidation [ 4 ]. Moreover, many of the previously conducted studies have confirmed the perturbing effects of FAs or their cellular intermediates, on the insulin signaling pathway [ 5 ], whereas palmitic acid is commonly applied to evoke IR in both animals [ 6 ] and cell lines [ 7 ].…”

“…Furthermore, the existence of a positive correlation between intramyocellular lipids content and the degree of insulin resistance has been strongly established in the scientific literature. In addition, triacylglycerol (TG) and diacylglycerol (DAG) are probably the two most commonly discussed, with respect to lipid-induced deterioration of insulin sensitivity, lipids fractions [ 4 , 8 ]. Interestingly, some research has indicated that the accumulation of a various size cytoplasmic lipid droplets occurs also in the diabetic rat's salivary glands [ 9 , 10 ].…”

Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α)

“…At the transcriptional level, several hormone nuclear receptors regulate the transcription of genes encoding for fatty acid oxidation enzymes, including PPARγ and ERRα [2]. The assembly of co-activators, such as peroxisome proliferator activator receptor gamma-coactivator 1a (PGC-1α), plays an essential role in enhancing the ability of these hormone nuclear receptors to drive transcriptional programs [3]. The expression of PGC-1α is controlled by the transcription factor CREB [4].…”

The Implication of PGC-1α on Fatty Acid Transport across Plasma and Mitochondrial Membranes in the Insulin Sensitive Tissues

“…Furthermore, the impaired lipid utilization, characterized by increased triacylglycerols (TAG) and other bioactive lipid fractions levels, such as fatty acyl CoA, diacylglycerols (DAG) and ceramides (CER), admittedly contributes to adverse alternations in insulin signaling pathway (Erion et al, 2016 ). Briefly, DAG stimulate protein kinase C (PKC-θ, PKC-βII, and PKC-δ isoforms) that in turn dephosphorylates IRS-1, thereby blocking phosphatidylinositol-3 kinase (PI3K) activation (Szendroedi et al, 2014 ; Łukaszuk et al, 2015a ). Excessive accumulation of CER induces phosphatidyl phosphatase 2A (PP2A) and protein kinase C λ/ζ (PKCλ/ζ), thus inhibiting the phosphorylation of PKB/Akt in the position of Thr308 and Ser473 (Hage Hassan et al, 2014 ; Kurek et al, 2015 ).…”