Hope Molecule

PGC-1α - a Key Regulator of Energy Metabolism 

The Hope Molecule - PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator-1α) is a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis (Liang H & Ward WF, 2006). 

PGC-1α is considered an important factor in controlling mitochondrial health. It’s also essential for energy metabolism, circadian rhythms, blood pressure, fat metabolism, and balancing cholesterol levels. 

PGC-1α stimulates mitochondrial biogenesis and promotes the remodeling of muscle tissue to a fiber-type composition that is metabolically more oxidative and less glycolytic in nature, and it participates in the regulation of both carbohydrate and lipid metabolism. It is highly likely that PGC-1alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes. 

It’s called the Hope Molecule and is released when muscles contract. It appears to be associated with mood, depression, central nervous system problems and inflammation. 

Potential supplements that may increase PGC-1α: 


It appears that resveratrol may stimulate an overexpression of PGC-1α, which would be a proposed way to reduce neurological inflammation (Yang X et al, 2017). It would do this by helping control microglia, which are the main cells that promote immune system function within the central nervous system. 

Pyrroloquinoline quinone (PQQ), a redox cofactor available as a dietary supplement, appears to have at least three central biological effects with powerful downstream health and longevity consequences: it stimulates the generation of PGC1-alpha, results in expression of SIRT3, and induces mitochondrial biogenesis. After brief recapitulation of background, I review some of the key research literature involved. Of possible practical significance, supplementation with PQQ could possibly offer the benefits of exercise in a pill.

L-citrulline has demonstrated to upregulate PGC-1α in skeletal muscle, which led to increased skeletal muscle weight that helps to improve time to exhaustion during exercise (Villareal MO et al, 2018). 

L Leucine is a branched amino acid that has an anti-obesity effects on glucose tolerance, lipid metabolism, and insulin sensitivity. Leucine helps control mitochondrial dysfunction which would help in the aging process, cardiovascular health and weight control. 

It has a role in both lipid metabolism and energy homeostasis in vivo and in vitro by acceleration of fatty acid oxidation, lipolysis, activation of the adenosine 5′- monophosphate-activated protein kinase (AMPK)–silent information regulator of transcription 1 (SIRT1)–proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, synthesis, and/or secretion of adipokines and stability of the gut microbiota (Zhang L et al, 2020). 

HMB supplementation stimulates AMPK indirectly by elevating adiponectin levels, resulting in the suppression of mTOR signaling, which subsequently inhibits fatty acid synthesis and promotes lipolysis, decreasing the total weight of fat in a growing pig model. 

Leucine and HMB may together modulate mitochondrial biogenesis and FAO via the AMPKα–SIRT1–PGC-1α axis in the adipose tissue. 

Alpha Lipoic Acid 

The metabolic action of alpha lipoic acid is mediated by activation of adenosine monophosphate-activated protein kinase (AMPK), which is a cellular energy sensor that can regulate peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). 

It was hypothesized that LA improves energy metabolism and mitochondrial biogenesis by enhancing AMPK-PGC-1alpha signaling in the skeletal muscle of aged mice (Wang Y et al, 2010). It was shown that alpha lipoic acid improves skeletal muscle energy metabolism in the aged mouse, which may be due to enhancing AMPK-PGC-1alpha mediated mitochondrial biogenesis and function. 

Alpha lipoic acid increases lean mass loss possibly by suppressing protein synthesis in the skeletal muscle by down-regulating the mTOR signaling pathway. Thus, LA may be a promising supplement for treatment of obesity and/or insulin resistance in older patients. 

Ubiquinol-10 (CoQH2) is a reduced form of coenzyme Q10 (CoQ10) has been shown to enhance mitochondrial activity by increasing levels of SIRT1, PGC-1α, and SIRT3 that slow the rate of age-related hearing loss and protect against the progression of aging and symptoms of age-related diseases (Tian G et al, 2014). 

Medium Chain Triglycerides (MCTs) are popular with the keto diet. It has been shown that they significantly increase protein levels of PGC-1α and ATP5α (Wang Y et al, 2018). This indicates that MCT improves skeletal muscle function through the induction of mitochondrial biogenesis and metabolism under high temperature condition. 

Vitamin C 

There are mixed results on vitamin C and other antioxidant effects on PGC-1α. “Yfanti et al., who observed no increase in PGC-1α expression, speculate that the result may be induced by different training modalities and the applied dose of vitamin C of 500 mg(74)versus 1000 mg in the rest of the relevant studies(16, 45, 53)” (Mankowski RT et al, 2015). 


Studies have shown to increase cytosolic calcium in myotubes, which promotes peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis (Wright DC et al, 2007). These results suggest that cytosolic calcium in skeletal muscle while exercising may mediate the exercise-induced increase in mitochondria. 

Acetyl L carnitine administration resulted in peroxisome proliferator-activated receptor γ coactivator-1α and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism (Hota KB et al, 2012). 

Rhodiola rosea 

Salidroside is an active component of Rhodiola rosea with documented antioxidative properties (Xing S et al, 2014). It was shown to increase mitochondrial mass and upregulate the mitochondrial biogenesis factor (PGC-1α). 

Other compounds that have potential to increase PGC-1α: 

Green tea EGCG, Gotu Kola, Quercetin, Grape Seed Extract, Epimedium, L Carnitine, Forskolin, Red yeast rice and Hydroxytyrosol

This report is for educational purposes only and is not intended to diagnose, treat, cure or prevent any disease. 

Return to Articles