PGC-1alpha gene and physical activity in type 2 diabetes mellitus
Exercise and sport sciences reviews 2006 ; 34: 171-175.
PubMed ID : 17031255
Type 2 diabetes mellitus is becoming increasingly common in both adults and in children. Uncontrolled hyperglycemia, the cardinal feature of type 2 diabetes, can cause serious microvascular and macrovascular complications, which include lower-limb amputation, kidney failure, heart disease, periodontal disease, and blindness. Although family-based studies indicate that genetic factors increase type 2 diabetes susceptibility, the allelic structure of most populations has not changed sufficiently during the past century to explain the corresponding rise in disease prevalence. By contrast, the declining physical activity levels and the changes in dietary patterns during this period are likely to be major etiological factors that underlie this phenomenon. However, not all those who are physically active have healthy metabolic profiles (5). In lifestyle intervention studies, considerable heterogeneity exists in the metabolic response of participants (2,3), yet the variability among family members is often less than among unrelated individuals (2). Taken together, these lines of evidence indicate that inherited factors, such as genes, interact with diet and physical activity to modify the risk of type 2 diabetes.
Of the many plausible physical activity interaction genes for type 2 diabetes, the peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) and the protein it encodes (PGC-1α) stand out as particularly interesting candidates. This is because PPARGC1A gene expression increases in response to exercise, the coding regions of the gene are polymorphic, and the PGC-1α protein coactivates a large array of transcription factors that are involved in cellular energy metabolism.
Although transcription factors directly bind to specific DNA sequences, they are typically incapable of forming functioning protein complexes by themselves because they lack the specific enzymes necessary to manipulate chromatin, unravel DNA, and sequester RNA polymerase II. Transcriptional coactivators, such as PGC-1α, are multiprotein complexes residing within the cell's nucleus that can be recruited by transcription factors via cellular signals to facilitate transcription. Thus, in combination, transcription factors and transcriptional coactivators powerfully control many aspects of metabolism.
PGC1α was the first of three PGC-1 homologues to be discovered, the others being PGC-1β and PGC-related coactivator 1. PGC1α and PGC-1β share high sequence homology, whereas PGC-related coactivator 1 is more distinct. PGC1α mRNA is expressed predominantly in tissues with high metabolic activity, most of which are rich in mitochondria. These include heart, exercising high-oxidative (type 1) skeletal muscle fibers, brown fat, kidney, liver, brain, and other tissue such as white adipose. PGC1α was initially identified as a cold-inducible coactivator in brown adipose tissue and skeletal muscle, where it controls adaptive thermogenesis via oxidative metabolism and mitochondrial biogenesis. However, it is now known that all three PGC-1 homologues are highly versatile, with the ability to dock to a wide variety of transcription factors in various tissue types and, by consequence, facilitate a broad and complex array of metabolic processes, which include oxidative metabolism, muscle fiber-type formation and switching, glucose and lipid transport, and hepatic glucose production.
Silencing of the PGC-1α signaling cascades results in reduced oxidative capacity and metabolic derangements that manifests as an insulin resistance-like syndrome. This includes hepatic steatosis, lower mitochondrial volume density in type 1 fiber, reduced mitochondrial respiration in muscle and liver, and growth retardation of heart and soleus muscle. Furthermore, PGC-1α null mice frequently die during the postnatal period, and those that survive respond poorly to the physiological stressors associated with cold and with exercise. In humans, the expression of the PGC-1α-coactivated genes is lower in the skeletal muscle of patients with type 2 diabetes compared with the skeletal muscle of healthy, glucose-tolerant individuals. Thus, it has become apparent that PGC-1α is a master regulator of many diabetes-related molecular pathways and regulates both basal and exercise-induced control of energy metabolism.
This review aims to describe the ways in which many important beneficial effects of physical activity on energy homeostasis are associated with the activation of the PGC-1α gene and to outline how functional variation at this locus could modify the effects of physical activity on the phenotypic antecedents of type 2 diabetes.