SR-9011: The next-gen metabolic activator igniting the research community
SR-9011 is a second-generation activator of the Rev-ErbA receptors which are found abundantly in liver, skeletal muscle, fat tissue, and the brain, where they function to promote normal development and circadian regulation of these tissues.
Key Research Findings:
Reductions in body fat and improved blood lipid/glucose profiles 
Anticancer function 
Increased basal oxygen consumption in muscle 
Decreased lipogenesis (ie. fat storage in cells) 
Increased mitochondrial content in muscle cells 
Lowers inflammatory cytokine levels in microglia (immune cells in the brain) , 
The link between your body clock & your metabolism
Although it may seem surprising, there is a strong link between your internal circadian rhythm and proper metabolic function. In mammals, almost all tissues display a self-sustaining molecular “pacemaker” that is responsible for aligning rhythms in various physiological functions.
Physiological processes involving metabolism and behavior, e.g., sleep/wake cycles, activity/rest cycles, are generally organized on a cycle of ~24 hours controlled by a circadian rhythm. The nuclear receptors Rev-ErbA and Rev-ErbB regulate the levels of core “clock proteins” and thus help to modulate the circadian rhythm.
Blood glucose levels and hormones such as insulin and glucagon also exhibit daily variations. Alterations in circadian rhythms are associated with metabolic disturbances and pathologies such as obesity and diabetes. The molecular components of these internal clocks and their regulatory mechanisms are well established. Among the different clock genes, Rev-ErbA is considered one of the key links between circadian rhythms and metabolism specifically.
Desynchronization of the body’s clock or misalignment between circadian rhythm and metabolism contributes to the development of chronic metabolic and cardiovascular diseases . In experimental models, knockout and mutations in clock genes that lead to the disruption of circadian rhythms have revealed the tight link between the circadian clock, fat tissue and metabolism .
Modulation of Rev-ErbA/B gene activity by synthetic activators (eg, SR9009 and SR9011) changes the levels of genes involved in fat and glucose metabolism and thus plays an essential role in maintaining the energy balance. Effects of SR9009 and SR9011 observed via in vitro and in animal studies are the following: increased basal oxygen consumption, decreased lipogenesis (ie. fat synthesis), decreased cholesterol and bile acid synthesis in the liver, increased mitochondrial content (ie. stronger oxidative capacity), increased glucose and fatty acid oxidation in the skeletal muscle, and decreased lipid storage in adipose tissues , , , , .
Importantly with regards to anabolic growth cycles, GH secretion is tightly regulated by circadian rhythms, so an improper rhythm will inhibit optimal GH secretion regardless of optimal nutrition and training –. Thus, there is a special interest in “resetting the clock” in the strength training industry.
The role of SR-9011 target Rev-ErbA in inflammatory diseases
Inflammatory diseases often times exhibit time-varying severity or symptoms. For instance, patients with rheumatoid arthritis show cyclical variations in symptoms, which frequently manifests as joint pain, stiffness and functional disability in the morning , .
Recent research has demonstrated that a high fat, high sugar diet is associated with chronic activation of microglia (immune cells in the brain) which contributes to disturbed energy homeostasis and diet-induced obesity . Microglia are the resident immune cells of the central nervous system and, depending on the brain region, they represent ~10% of total cell population. Microglia continuously monitor the surrounding tissue to sense alteration of brain functions and are involved in controlling neuronal excitability, synaptic activity, neurogenesis, and clearance of apoptotic cells in the healthy adult brain. Additionally, microglia show a clear day/night rhythm when animals are fed a regular diet, but this rhythm is disrupted in diet-induced obesity.
These findings suggest that the daily microglia rhythm is important for its normal activity and disturbance may result in metabolic diseases. However, little is known about the mechanism behind the intrinsic clock and the function of microglia. There is also a complex interplay between metabolic processes and immune responses, known as immunometabolism, in which metabolic reprogramming underlies the inflammatory state of microglia. Therefore, considering the important role of Rev‑ErbA in the molecular clock machinery, neuroinflammation, and metabolism, ongoing studies are leveraging the Rev‑ErbA agonist SR9011 to further explore the beneficial role of Rev‑ErbA in brain cell metabolism , .
The role of SR-9011 in future tumor therapy?
Little is known about the circadian clock function of tumor cells specifically. Nevertheless, the pharmacological manipulation of circadian components might allow for new anticancer strategies. Molecular clock disruption/modulation is known to influence the development and progression of cancer . Generally speaking, the circadian rhythm can be targeted in three main ways: by optimizing the circadian lifestyle (“training the clock”), by optimizing the timing of therapy (“clocking the drugs”), or by targeting specific circadian clock components (“drugging the clock”) .
Recent approaches have attempted to directly target mammalian circadian clock components (i.e., CRYs, Rev-ErbA/B, and RORs) using small molecules. Patients with low Rev‑ErbA levels exhibit poor prognosis compared with patients with high levels, indicating Rev‑ErbA as a prognosis factor for gastric cancer . Rev‑ErbA activation induces cancer cell death in human gastric cancer and in preadipocytes .
Anti-proliferative effects of Rev‑ErbA have been observed in human breast and gastric cancer cells. Activation of Rev‑ErbA suppresses proliferation of breast cancer cells regardless of ER or HER2 status. Thus Rev‑ErbA appears to pause the cell cycle in tumor cells, limiting their growth , .
Recently, a paper in the high-impact journal Nature has argued that pharmacological targeting of Rev‑ErbA is a promising strategy for cancer treatment . The anticancer activity of SR9009 and SR9011 (two Rev‑ErbA activators) modulates a number of crucial tumor drivers (such as HRAS, BRAF and PIK3CA). Activation of Rev‑ErbA causes cancer cell death but does not affect the viability of normal cells .Mechanistically, Rev‑ErbA suppresses fat biosynthesis through suppression of two key rate-limiting enzymes (fatty acid synthase and stearoyl-CoA desaturase).
As a potent activator of Rev‑ErbA, SR-9011 is an exciting molecule that has been the subject of numerous high-impact studies investigating it’s potential role in reducing body fat, normalizing blood lipids and sugars, increasing oxygen consumption and mitochondrial function in skeletal muscle. Most excitingly, it is moving towards being trialed as an anticancer agent for the therapy of breast, brain and gastric tumors.
*The information herein is for educational and informational purposes only. THIS PRODUCT IS FOR RESEARCH USE ONLY. For use in animal studies, all research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).
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