Supporting AMPK Activation for Metabolic Health: A Practical Guide

By Kelly C. Heim, Ph.D.

This article offers insight into metabolic health and how to support AMPK activation.

Exercise regularly. Reduce calorie intake. Eat a balanced diet rich in fruits and vegetables.

Sound familiar?

This well-worn advice is older than most of our readership, but the underlying health-promoting mechanisms are more sophisticated than many modern medicines. Evolving research has deepened our understanding of the “how and why” behind lifestyle interventions for metabolic health, an area of endocrinology that encompasses insulin and glucose homeostasis, energy balance and body weight. Ample epidemiological, observational and prospective clinical trial data show that low-calorie diets and/or exercise programs enhance metabolic homeostasis in fairly predictable and partially redundant ways.

Exercising and fasting seem like different activities, but their effects converge and cooperate in signaling healthful changes in our metabolism, supporting beneficial adaptations that render cells more resilient and efficient. Exercise, calorie restriction and certain phytochemicals in plants activate AMP-activated protein kinase (AMPK), an energy “sensor’ that researchers describe as “the guardian of metabolism.”¹

AMPK is activated whenever there’s an energy shortage. In these situations of “energetic stress,” the levels of cellular energy currency (adenosine triphosphate, or ATP) are low, while AMP (“spent” ATP) levels are high. This low-energy state (a low ATP:AMP ratio) potently stimulates AMPK, signaling the body to ramp up energy production and stop wasting fuel on frivolous affairs like cell growth and fat synthesis. Perhaps the most impactful and measurable short-term effect is insulin sensitization, which becomes noticeable when these healthy habits are sustained over several weeks to months. The effect is quite simple—AMPK ensures that glucose goes where it needs to (into cells where it can be utilized for energy) instead of circulating idly in the bloodstream.^{1, 2}

Meeting energy demands is the specialty of mitochondria (famously called the “energy powerhouses”), which occupy the cytosol of a single cell, sometimes by the hundreds to thousands. AMPK ensures that mitochondria increase in number when there’s an energy deficit (a process called mitochondrial biogenesis) and that old and damaged ones are removed (known as mitophagy). In simple terms, AMPK helps to refurbish mitochondrial networks, much like replacing all the light bulbs in your home. Healthier mitochondria support the net movement of glucose into cells (Figure 1).^{1, 3}

Figure 1. The AMPK-SIRT1 axis supports glucose uptake by cells. AMPK activates sirtuin 1 (SIRT1) and PPAR-gamma coactivator 1 alpha (PGC-1α) to induce mitochondrial biogenesis, which supports the function of insulin after it binds to its receptor (1), encouraging the movement of glucose transporters to the membrane (2) where glucose enters the cell to be used for energy. Image created with BioRender.com.

The benefits of AMPK activation go far beyond glucose disposal. AMPK promotes autophagy (derived from the Greek phrase “eating of self”), a process that degrades dysfunctional cells and allocates their parts and substrates toward the repair, fueling and restoration of healthier cells.⁴ The AMPK-SIRT1 axis is a major conduit by which caloric restriction (CR) prolongs lifespan and “healthspan” (the duration of optimal health over the lifespan) in multiple animal models.⁵

Some of the adaptations elicited by AMPK curtail energy-consuming processes, like cell growth and fat synthesis. For example, AMPK inhibits the proliferation of smooth muscle cells that line arteries by arresting them in the middle of the cell cycle, which helps to maintain the normal thickness of the vessel wall.^{1, 6} AMPK also reduces hepatic cholesterol synthesis by inhibiting HMG CoA reductase and interferes with enzymes that synthesize fatty acids in adipose tissue.

In skeletal muscle, AMPK slows cell growth (hypertrophy). This is a temporary state that switches to anabolism when a meal is consumed.  Paradoxically, AMPK activation may support post-prandial anabolism and protein synthesis by improving the insulin sensitivity of muscle cells.  Therefore, athletes trying to build muscle should include periods of low-energy intake or fasting as part of their dietary regimen. After all, insulin is the most powerful anabolic hormone in mammals. Taking advantage of AMPK could be as simple as cutting out snacks between meals or extending the overnight fasting period.

Practical Ways to Boost AMPK

• Stop snacking. Allow the body to enter a mini-fast between meals (at least 6 hours). Exercising during this time, even if it’s a 10-minute walk, will expedite the onset of the energy deficit that’s needed to activate AMPK. Walking for just a few minutes after a meal, and even taking standing breaks while sitting, can kickstart this energy shift.⁷
• Caloric restriction (CR) is the most extensively studied dietary method to up-regulate AMPK. Ample research has shown that limiting calorie intake, even modestly, enhances insulin sensitivity and metabolic regulation.^{1, 8} In practice, caloric restriction is difficult to deploy because of low patient compliance. Alternative protocols involving alternate day fasting (ADF) may offer similar health benefits with better long-term adherence.⁸ Modest reductions in overall energy intake can also activate AMPK, but it’s important to allow blood sugar to drop sufficiently between meals to engage it. 
• Exercise is perhaps the most sustainable and well-supported method. Any exercise will suffice, as long as it burns calories and creates a temporary energy deficit. It’s important to avoid snacking before or during the workout. 
• CR mimetics (CRMs) are small molecules that may partially recapitulate the cellular effects of CR.^{9, 10} CRMs lacked a unified definition until 2014 when Madeo and colleagues defined them as substances that inhibit protein acetylation, which “tunes up” metabolism, mitochondrial renewal and longevity pathways.⁹ To learn more, here is a short article describing CRMs.
• Resveratrol has been shown to support the AMPK/SIRT1 axis and mitochondrial function at daily doses of at least 150 mg/day.^{11, 12‡}
• Berberine supports insulin receptor function and signaling, in part, by supporting AMPK activation. Human clinical trials have shown significant metabolic health benefits after 4-12 weeks of daily supplementation with 1000-1500 mg/day.^{13, 14} Berberine has very poor oral bioavailability, but new delivery systems can overcome this limitation. Berbervis^® phytosome is 4x more bioavailable than a standard berberine formulation.^15‡
• Nicotinamide riboside and nicotinamide mononucleotide (NMN) support metabolic health by mimicking a low-acetylation state. By supplying NAD+, they directly activate SIRT1. NAD+ is made from dietary niacin and its biosynthesis declines with age.^5‡
• Polyphenols in fruits, berries, green tea and other plant foods support the AMPK-SIRT1 axis and other pathways related to cardiometabolic health.^16‡

Summary & Key Points

• AMPK is a master metabolic sensor that enhances mitochondrial function, insulin signaling and glucose metabolism.
• Lifestyle interventions that create energy deficits, such as caloric restriction and exercise, are well-established modalities that activate the AMPK-SIRT1 axis.
• Various phytochemicals, such as polyphenols from fruits and vegetables and resveratrol and berberine, also support AMPK and/or SIRT1 activity.

For Further Learning

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References

1. Herzig S, Shaw R. Nat Rev Mol Cell Biol 19, 121–135 (2018). 
2. Burkewitz K, Zhang Y, Mair WB. Cell Metab. 2014 Jul 1;20(1):10-25.
3. Smith BK, Steinberg GR. Curr Opin Clin Nutr Metab Care. 2017 Jul;20(4):248-253.
4. Nakamura S, Yoshimori T. Autophagy and Longevity. Mol Cells. 2018 Jan 31;41(1):65-72.
5. Dai H, Sinclair DA, Ellis JL, Steegborn C. Pharmacol Ther. 2018 Aug;188:140-154.

Weight Management

Webinar: “Weight Management: Why It Matters & What to Do About It” with Dr. Caroline Cederquist

Associated material: PureLean Exclusive, PureLean Brochure, PureLean Course

VIEW THE WEBINAR

This blog explains the vital importance of how integrating weight management into your practice by first establishing foundational care and then adding in personalized approaches for your patients can help address their needs.

The Importance of Weight Management?

“Paradoxically coexisting with undernutrition, an escalating global epidemic of overweight and obesity—“globesity”—is taking over many parts of the world. If immediate action is not taken, millions will suffer from an array of serious health disorders.” – World Health Organization¹

Obesity and weight gain are an epidemic, with around 70% of the US population currently considered overweight or obese with the prevalence rising 30-40% over the past two decades³.

As the WHO points out, obesity is a risk factor for many chronic conditions, including heart disease, high blood pressure, dyslipidemia, diabetes, fatty liver, sleep apnea, osteoarthritis, kidney disease, and much more. The silent symptoms not commonly reported can also include the psychosocial stress associated with being overweight or obese.¹

In her lecture, Dr. Caroline Cederquist⁺ makes the case for Functional and Integrative medical practices to take the lead on offering weight management support for patients: “Weight management is not often addressed in the traditional medical model … [doctors] don’t have the time and the setup to really work somebody through the lifestyle adjustments that are needed to make this happen, and if 80% of functional medicine is lifestyle adjustment, then weight management really should be at the top of the list because it affects so many other medical conditions that follow it.”

She suggests establishing foundational interventions for weight management in your practice, and then adding methods of personalization to optimize care for individual patients.

Foundational Interventions

Caloric Restriction

The first step when integrating caloric restriction in your weight management plan is myth-busting—it is not about diets or only eating certain foods. Options like ketogenic or plant-based may not be appropriate for your patient, and it is vital to create an approach to food that is going to give them enough fuel to get through their day, without overloading them on calories.

Diet Higher in Protein

In order to ensure the highest quality of calories, it is crucial to establish a higher intake of protein. Reduced-calorie diets higher in protein have repeatedly been associated with healthy weight management, satiety, and body composition. Think of this like a scale—as the total amount of calories decreases each day, the amount that comes from protein must increase.

Standard diets recommend 15% of daily calories come from protein, which won’t be sufficient if overall calories are restricted. Dr. Cederquist recommends 100-140g of protein per day based on the patient’s body composition and lifestyle. While this may initially seem high, eating > 100g protein per day is associated with enhanced body composition, reduced risk of regain, and preservation of lean muscle mass.

Diet Higher in Fiber

Adequate dietary fiber supports healthy weight, satiety, cardiovascular function, the microbiome, and the innate immune response. Unfortunately, only around 5% of Americans consume the recommended amount of fiber.

When working on weight management with your patients, be sure to set reasonable expectations for increasing fiber in their diets.

Dr. Cederquist keeps it simple by suggesting two fruits and a minimum of three non-starchy vegetables per day to increase fiber and support satiety while maintaining low caloric intake.

Micronutrient Repletion

Weight gain causes stress on the body is associated with lower plasma concentration of essential vitamins and minerals. When reframing dietary intake, it is vital to ensure proper levels of micronutrients. If it is not possible or difficult to meet this need by diet alone, many patients find it convenient to take a well-balanced multivitamin to supplement micronutrient levels.

Regular Exercise

After the nutritional aspects of your weight management plan is in place, then you can begin the conversation on exercise. Exercise is more than simply burning calories; healthy levels of exercise activate AMPK and SIRT1, improves vascular function, and decreases fat in visceral adipose tissue. Of course, exercise has many mental health benefits as well, which can be helpful in offsetting the stress and pressure associated with weight.

Personalizing Your Care

Lab Assessments

Lab assessments don’t have to be complicated, and Dr. Cederquist recommends starting with 10 basic tests to help understand weight management patients:

• Complete Blood Count (CBC)
• TSH, Free T3 and Free T4
• Comprehensive Metabolic Profile (CMP)
• Serum Vitamin B12
• Fasting Serum Insulin
• 5-hydroxy Vitamin D
• HbA1c
• Magnesium RBC
• Lipid Profile

These tests are commonly available through services such as LabCorp® and Quest®.

Genetic Assessments

An additional test gaining popularity is a genetic test. Whether your patient has completed an at-home testing kit or you would like to order one through your lab, genetic testing can help answer important questions for those establishing a weight management care plan.

PureGenomics® is a complimentary service which offers a science-backed nutritional genomic assessment based on insights from genetic variants associated with weight management, glucose metabolism, exercise response, and other metabolic aspects of health.

Additional Assessments

The final aspect of Dr. Cederquist’s approach to weight management is to address insulin function and metabolic rate.

Regarding insulin function, Dr. Cederquist found almost 90% of the people in her clinic had labs indicating problems with insulin function. She says understanding the status of insulin function “has been the cornerstone of my medical weight loss practice in terms of really getting our patients to buy into the adequate protein and controlling the carbohydrate content—that they have to switch from high-starch carbs to more vegetables and lower glycemic carbohydrates and continuing to keep fat intake at a normal range.”

Sometimes, even when the patient does everything right, they still have a hard time getting their weight where they want it. These patients might say their metabolism is “broken” or “not what it used to be”. Of course, our bodies age and change, but to assess if metabolism is to blame for lackluster results, you can use an indirect calorimeter. This tool compares CO₂ intake to CO₂ output to give you metabolic rate which can help establish an understanding of metabolic rate in your patients.

Dr. Cederquist also acknowledges the important role of sleep and stress in weight management. Poor sleep and elevated stress can be related to weight gain and/or poor dietary choices. Studies have shown overtired individuals have increased levels of the “hunger hormone”, ghrelin, as well as increased salt retention, decreased levels of leptin, and decreased insulin function. To support healthy sleep habits and to lower stress levels, regular exercise can be helpful, as long as it is not within one hour of bedtime or it may interfere with sleep.

Conclusion

Achieving healthy weight management is rarely quick or simple, and often requires time and effort from both you and your patient. Dr. Cederquist’s approach helps to create a coachable care plan that will help you and your patient on the path to success by establishing a foundation and layering in personalized care for your patients.

For additional information, or to learn more, please visit our PureLean Exclusives found here.

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Works Cited

1. “Obesity and Overweight.” World Health Organization, World Health Organization, https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
2. Mitchell NS, Catenacci VA, Wyatt HR, Hill JO. Psychiatr Clin North Am. 2011;34(4):717-732
3. Fast Stats: Obesity and Overweight. National Center for Health Statistics. Last reviewed Feb 2020.
4. Pi-Sunyer X. Postgrad Med. 2009;121(6):21-33.
5. Moon J, Koh G. J Obes Metab Syndr. 2020;29(3):166-173.
6. Westerterp-Plantenga MS, Lejeune MP, Nijs I, et al. Int J Obes Relat Metab Disord. 2004 Jan;28(1):57-64.
7. Manninen AH. J Int Soc Sports Nutr. 2004;1(1):45-51.
8. Quagliani D, Felt-Gunderson P. Am J Lifestyle Med. 2016;11(1):80-85.
9. Hosseini, B, et al. Biol Trace Elem Res. 2016 Jun 22.
10. Amara NB, et al. Genes Nutr. 2014 Jul;9(4):410.
11. Gardner C, et al. Am J Clin Nutr. 2010 Aug; 92(2): 304–312.
12. Li. et. al. Inter J of Obes. 2010. 34; 1070-1077.
13. Dias, K. A., Green, D. J., Ingul, C. B., et al. Pediatrics, 2015. 136(3), e648-e659.
14. Goedecke, J. H., & Micklesfield, L. K Medicine and Sport Science, 2014. 6082-93.
15. Cooper CB, Neufeld EV, Dolezal BA, Martin JL. BMJ Open Sport Exerc Med. 2018;4(1):e000392.

PureGenomics® nutritional information is not intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease.
LabCorp® is the registered trademark of Laboratory Corporation of America. Pure Encapsulations is not affiliated with or endorsed by LabCorp®.
Quest® is the registered trademark of Quest Diagnostics. Pure Encapsulations is not affiliated with or endorsed by Quest®.

⁺Dr. Caroline Cederquist is a retained advisor for Pure Encapsulations®.