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SARMs & Weight Loss: MK-2866 + Cardarine

Although the goal of Selective Androgen Receptor Modulator (SARM) research has historically aimed to boost lean body mass, scientists are increasingly curious about a possible role for SARMs in weight loss. Specifically, is it possible for SARMs to efficiently promote fat loss as part of an exercise regimen, rather than promote overall body mass gains? Given that most clinical research has thus far focused on strength and anabolic metrics, we need to consider SARM-adjacent research for insights into how to leverage SARMs for shedding pounds rather than building muscle. 

The good news is that there is plenty of evidence that increasing natural androgen levels can effectively promote weight loss, especially for those who are over their target weight by more than 30% [1]–[12]. Read on to discover why a stack containing MK-2866 plus Cardarine may prove to be the optimal SARM-oriented solution for weight loss to be elucidated by emergent clinical trials.

First, it is important to recall that SARMs function by mimicking the action of androgens (ie. testosterone) in selective tissues of the body, and it turns out that androgens actually affect a much broader array of tissues than you might think. For instance, one of the target tissues of testosterone is the brain, where it functions in part to modify behavior. Moreover, it turns out that behavioral adaptation in response to increasing androgens is an exciting area of ongoing research.

Being overweight is largely a consequence of behavior (ie. lack of motivation to exercise, lack of motivation to curb overeating, etc). Intriguingly, research has shown that raising testosterone levels in the brain causes positive behavioral changes that make losing weight easier. So why not just inject testosterone or use testosterone creams? Unfortunately, the negative side effects of testosterone replacement therapy (TRT) (acne, risk of blood clots, testicle shrinkage) in addition to the more serious cardiovascular riskshave made physicians reluctant to prescribe androgens [13]. Fortunately, the improved safety profile of SARMs vs conventional androgens offers a better alternative [14].

SARMs Reinforce A Neurobehavioral Positive Feedback Cycle

If you are overweight, then losing those unwanted pounds will require behavioral changes that are driven primarily by being accountable to yourself and your goals. Moreover, successful behavioral changes need to be reinforced via neurobehavioral plasticity in order for habits to become second nature. Fortunately, research has shown that androgens promote self-accountability and neurobehavioral reinforcement due to their positive effect on promoting social competition and motivation [15]–[17]

Accumulating evidence show that androgens modulate the motivation to complete goals via actions on the mesocorticolimbic dopaminergic system in the brain. Work in animals has so far supported this assumption by identifying the neurobiological pathways linking testosterone, and its primary metabolites 5α-dihydrotestosterone (DHT) and estradiol to several brain regions of the dopaminergic system. For instance, fundamental neurobiological studies have demonstrated that dopamine neurons contain androgen receptors (AR) [18], and thus they can be activated by SARMs such as MK-2866.

In the brains of adolescent male rats, testosterone is also able to change—via direct action at AR—the levels of dopamine receptors, and levels of the dopamine transporter protein, which regulates dopamine availability [19], [20]. These groundbreaking studies provide solid peer-reviewed evidence to back up the anecdotal evidence of SARMs promoting a key positive feedback loop of weight loss: motivation to lose weight, followed by exercise and dietary changes, reinforced by the dopamine reward system, thus promoting a continuing motivation to lose more weight (Fig. 1). 

Graph of SARMs such as MK-2866 increase the levels of dopamine receptors and the levels of the dopamine transporter proteins in midbrain neurons, thus jumpstarting the positive feedback loop of motivation, behavioral change, and dopamine reward.
Fig. 1. SARMs such as MK-2866 increase the levels of dopamine receptors and the levels of the dopamine transporter proteins in midbrain neurons, thus jumpstarting the positive feedback loop of motivation, behavioral change, and dopamine reward.

Clinically, both men and women with suboptimal androgen levels exhibit apathy and lack of motivation for self-improvement (ie. weight loss) [21]. Intriguingly, even single-dose androgen administration in healthy subjects increases motivation to engage in cued behaviors and increases BOLD activation in the ventral striatum (ie. Blood-oxygen-level-dependent imaging in the part of the brain important for reward behavior) which is most pronounced in individuals with low motivation [22]. Thus, if your low motivation to lose weight is hampering your efforts, activating AR via SARMs can potentiate the induction of the dopamine induced positive reinforcement of the necessary behavioral changes to keep shedding pounds.

SARMs To Help You Compete Against Yourself

The most successful athletes (ie. those who are among the fittest people on earth) have learned to continually push themselves by setting progressive goals. This phenomenon can be thought of as self-competition, and it is crucial to main consistent results [23]. An interesting and open question is the role of androgens a self-competition. 

Evidence supports a role of androgens in this regard by showing that individuals’ level of self-efficacy, effort, and motivation are positively related to serum androgen levels in both men and women [24], [25]. Furthermore, successful achievements of effortful challenges (ie. successful weight loss) enhance motivation and increase the value of the achievement as reflected by increased dopamine signaling in the ventral striatum (ie. the midbrain) [26], which as we’ve discussed can be potentiated with SARMs such as MK-2866.

SARMs & Fat Oxidation (ie. Fat Burning)

In addition to boosting motivation to lose weight, SARMs can also promote fat oxidation by activating Androgen Receptors (AR) in numerous tissues and cell types. It turns out these receptors, which are activated by SARMs, are present not only in muscle tissues but also in adipose tissues (ie. fat cells) that consume and expend energy [27]. Previously it has been reported that blocking androgen hormone production decreases fat oxidation during acute exercise [28] which can be seen in Fig. 2. Thus, by deduction we know that the action of SARMs can promote fat oxidation in adipose tissues during exercise.

Recent findings from large clinical studies have shown that long-term androgen therapy in men can produces significant and sustained weight loss, substantial reduction in waist circumference and BMI and overall improvement in body composition. Further, androgen therapy ameliorates components of the metabolic syndrome. These improvements induced by Androgen Receptor have been attributed to improved mitochondrial function, increased energy utilization, increased motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity [1], [29], [30].

Graph of Fig. 2. Change in fat oxidation during 1 h of exercise. Energy metabolism measured during 1 h of exercise. Control, n = 8; Exercise, 60% VO 2 max, n = 8; Exercise + AR inhibitor, 60% VO 2 max, n = 8. Values are presented as means ± standard deviations (n = 8). Note that SARMs produce the opposite effect of AR inhibitors (P < 0.05). Adapted from Kim et. at. Nutrition & Metabolism, 2019;16:82
Fig. 2. Change in fat oxidation during 1 h of exercise. Energy metabolism measured during 1 h of exercise. Control, n = 8; Exercise, 60% VO 2 max, n = 8; Exercise + AR inhibitor, 60% VO 2 max, n = 8. Values are presented as means ± standard deviations (n = 8). Note that SARMs produce the opposite effect of AR inhibitors (P < 0.05). Adapted from Kim et. at. Nutrition & Metabolism, 2019;16:82 

According to a recently published review of ARs, androgens bound to the AR stimulate the induction of enzymes required for uptake of fatty acids released by lipolysis (ie. fat burning) from blood circulation and directly from adipocytes [31]Future investigations will be necessary to elucidate the effects of AR by particular SARMs on resting metabolism and determine a clear mechanism of increased fatty acids transport.

Cardarine: The Ideal SARM Companion to Supercharge Weight Loss?

What if your sincere desire to exercise in order to lose weight is hampered by lack of stamina and endurance necessary to burn calories? In this scenario, no SARM will be able to match the benefits offered by another compound, Cardarine, which is often misclassified as a SARM, but actually does not bind to AR. Instead, Cardarine binds to the PPAR family of gene regulators which promotes endurance capacity via aerobic glycolysis.

Graph of Fig. 3. Levels of Free Fatty Acids (FFA) in the blood of healthy individuals consuming 3 different doses of Cardarine: 2.5 mg, 5.0 mg, or 10 mg per day compared to placebo (P < 0.05). Adapted from Olsen et. al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:2289–2294
Fig. 3. Levels of Free Fatty Acids (FFA) in the blood of healthy individuals consuming 3 different doses of Cardarine: 2.5 mg, 5.0 mg, or 10 mg per day compared to placebo (P < 0.05). Adapted from Olsen et. al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:2289–2294 

In the above study, which is also consistent with preclinical models, a significant decrease in serum insulin was observed at the 2 lower doses of Cardarine, implying an improvement in insulin sensitivity. Moreover, a different study demonstrated that Cardarine can reduce liver fat [32](Fig. 4). Fatty liver is an extremely common problem that affects roughly 1 in 4 American adults. If you carry excess abdominal weight you probably have a fatty liver.

In the context of trying to achieve exercise-induced fat burning, fatty liver actually prevents overall weight loss, as demonstrated by a recent clinical study [33]. Thus, Cardarine’s effect on reducing fatty liver allows the body to more efficiently lose weight during exercise by enabling the liver to process fatty acids faster.

graphs of Fig. 4. Individual changes in percentage of liver fat content measured before and after drug treatments, including 10 mg per day of Cardarine. There was a statistically significant reduction in liver fat content in response to Cardarine treatment when the individual before-treatment liver fat content was used as covariate (P = 0.04). Adapted from Risérus et. al. Diabetes 2008 Feb; 57(2): 332-339
Fig. 4. Individual changes in percentage of liver fat content measured before and after drug treatments, including 10 mg per day of Cardarine. There was a statistically significant reduction in liver fat content in response to Cardarine treatment when the individual before-treatment liver fat content was used as covariate (P = 0.04). Adapted from Risérus et. al. Diabetes 2008 Feb; 57(2): 332-339

Conclusion

In order to lose weight, behavioral changes are always necessary. Research into the Androgen Receptor has provided valuable clues as to why SARMs like MK-2866 can supercharge fat burning. SARMs promote neurobiological plasticity and dopamine neuron reinforcement to jumpstart the positive feedback loop of motivation, exercise, and reward-satisfaction.

SARMs can also promote lipolysis/ fat oxidation in muscle and adipose cells. Finally, in order for your body to permit the cardio-metabolic endurance necessary to burn calories, Cardarine adds fuel to the fire by lowering free fatty acids and reducing fatty liver in order to allow your body to oxidize fat optimally. Excitingly, future clinical research will explore the underlying mechanisms responsible for the potent weight-loss combination of MK-2866 plus Cardarine.

*This information is for educational purposes only. These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease. 

References

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