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Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.

Abstract

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver.

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Vinegar has been used as a medical therapy for thousands of years. Hippocrates recommended it for cleaning wounds and mixing it with honey to suppress coughs. It’s an ingredient in Elliman’s Universal Embrocation, which has been used since the 1800s to relieve aches and pains, and it’s been touted as a treatment for everything from sunburn and dropsy (edema) to stomachaches and warts.

Though vinegar may not be as miraculous as some claim, there is one “old wives’ tale” that is real: its ability to lower blood sugar. In fact, recent research suggests that vinegar works in a manner similar to metformin (Glucophage), the world’s most widely used diabetes drug!

The Metformin Effect

We’ve known for years that when vinegar is taken with or just before meals, it inhibits enzymes necessary for the digestion of starches and other complex carbohydrates, thus preventing them from being broken down into glucose and absorbed into the bloodstream. Vinegar also slows gastric emptying, so it delays the uptake of glucose and other nutrients. The end result is a 20–35 percent reduction in postprandial (after-meal) blood sugar and insulin levels, as demonstrated in studies of both type 1 and type 2 diabetes as well as metabolic syndrome.

But when taken at bedtime, vinegar also lowers morning fasting blood sugars—and here’s where it really gets interesting. Vinegar stimulates an enzyme called AMP-activated protein kinase (AMPK) that is a key player in glucose and fat metabolism, insulin signaling, and energy balance. AMPK increases fat oxidation, improves glucose uptake and insulin sensitivity, and lowers gluconeogenesis, or glucose production in the liver, which is about three times higher in patients with type 2 diabetes than in healthy people.

AMPK is also the target of metformin. I rarely recommend oral diabetes medications—diet, exercise, weight loss, and targeted supplements work for most patients. But when I have to prescribe a drug, it’s metformin. Hands down, it’s the safest of the bunch, and unlike other oral diabetes meds, it doesn’t cause weight gain.

The discovery that vinegar shares a common mechanism with metformin has made me realize just how powerful a therapy this dirt-cheap kitchen staple can be—and its benefits don’t end with blood sugar control.

NO, Weight Loss, and More

Vinegar-induced AMPK activation boosts nitric oxide (NO) release in the endothelial cells lining the blood vessels. As I told you last month, NO relaxes the arteries, protects against atherosclerosis, and has positive effects in tissues throughout the body.

It facilitates weight loss by curbing appetite and stimulating fat burning. In a clinical trial conducted in Japan, overweight men and women were divided into three groups. Groups one and two drank beverages containing 15 or 30 mL (1 or 2 tablespoons) of apple cider vinegar with breakfast and dinner, while group three got a placebo drink. After 12 weeks, the first two groups had significantly greater decreases in weight (more than 4.4 pounds), body mass index (BMI), body fat ratio, and triglycerides compared to the placebo group. Although results were somewhat better in the participants who took the higher dose of vinegar, the researchers concluded that one tablespoon per day was enough to achieve benefits.

In animal studies, vinegar improves function of the beta cells in the pancreas that secrete insulin, and it reduces fat buildup in the liver (nonalcoholic fatty liver disease), which is a very common problem in people with diabetes and obesity.

When added to food, vinegar inhibits the formation of advanced glycation end products (AGEs), which contribute to inflammation and oxidative stress and are linked to diabetes and many of its related problems. Finally, its acidity increases the perception of saltiness and is being evaluated as a way for food manufacturers to reduce sodium content while maintaining flavor.

A Spoonful of…

We keep bottles of apple cider vinegar on the tables in the dining room where Whitaker Wellness Back to Health Program patients eat their meals, and we encourage everyone who has diabetes, metabolic syndrome, or wants to protect against these conditions to take a tablespoon or so with lunch and dinner.

No, vinegar doesn’t taste good. I wish I could just tell you to eat dill pickles or take vinegar pills, but a preliminary study showed that, unlike regular vinegar, neither was effective in reducing hemoglobin A1C in patients with diabetes. Sweeteners make it more palatable—as Mary Poppins says, “A spoonful of sugar helps the medicine go down.” Though I’d prefer you use xylitol or stevia, do whatever it takes to get your daily dose because, as you can see, vinegar is truly powerful medicine.

Recommendations

Aim for one or two tablespoons of vinegar, taken twice daily in divided doses, preferably with meals. Because vinegar is quite acidic, it should always be diluted. Add a little olive oil and seasonings and use it as a salad dressing. Or mix it in water, along with a healthy sweetener like xylitol or stevia—which dramatically improves the taste—and sip it slowly.
At the clinic, we use Bragg’s apple cider vinegar, which is sold in health food stores, but any type of vinegar will provide similar benefits.