Adiponectin, Ghrelin & Leptin. Major Hormones in Weight Loss Resistance

With obesity more prevalent now than ever, it goes without saying that we need to take action to halt this epidemic in its tracks. Many overweight people eat far too many calories while living a highly sedentary lifestyle that further exacerbates the problem at hand. Most people, however could be experiencing weight loss resistance where weightloss becomes difficult, even with proper diet and exercise. But what is it that causes these internal health ramifications? Research is showing that many of the health risks associated with obesity may, in fact, be derived from hormones secreted from adipocytes (fat cells), called adipokines. This chapter will give you an in-depth look at what adipokines are and how they impact weight loss and appetite.

What are Adipokines?

Adipokines are a distinct class of signaling molecules (hormones) produced by fat cells in the body. Many people assume that body fat is more or less an inert biological tissue that merely helps insulate the body, but as time goes on we are learning that fat tissue serves a much greater role. In fact, brown fat tissue is favorable in that it helps burn a greater amount of calories than white fat tissue (which is generally the type of fat tissue found in the abdominal region). Leaner individuals typically have a greater amount of brown fat tissue and a smaller amount of white fat tissue, and this gives them a healthier balance of adipokines.¹ The two primary adipokines secreted in humans are leptin and adiponectin, both of which are peptide hormones.

What is Leptin?

Leptin is a peptide hormone secreted mostly in white adipose tissue, thus it’s considered an adipokine (“fat hormone”). Leptin circulates in serum at concentrations proportion to a person’s body fat percentage. In other words, people who have more body fat tend to produce more leptin, while leaner individuals have lower amounts. The primary role of leptin is countering the actions of ghrelin - a gut hormone related to human growth hormone that stimulates appetite by increasing the expression of certain neuropeptides in the brain. In fact, this is why both growth hormone and ghrelin increase after extensive fasting, since they communicate to your brain that it’s time to eat. Leptin, on the other hand, helps reduce calorie intake and appetite by increasing the expression of neuropeptides that promote satiety.² It’s thought that people with anorexia have abnormally high leptin levels and this prevents them from feeling hungry or wanting to eat. Naturally, this makes many overweight people feel like leptin is the answer to losing weight, which is partially true. However, in the case of obesity, studies have shown that leptin signaling is impaired in a similar fashion as insulin resistance. This explains why overweight and obese people have a hard time controlling their food intake despite having a high amount of leptin.³ As such, it’s key to restore normal leptin receptor and signaling activity when trying to lose weight as this will help make it easier to control appetite and reduce food intake. The three most prudent ways to accomplish this are by eating a proper diet (particularly the keto diet), exercising, and using certain dietary supplements, which we will discuss later in this chapter.

Ghrelin and Appetite Regulation

Ghrelin is a peptide hormone produced in the stomach and pancreas. The primary action of ghrelin is binding to ghrelin receptors (throughout the gastrointestinal tract and parts of the brain) which stimulate the secretion of growth hormone from the pituitary gland and increase hunger signaling.^4,5 Both ghrelin and growth hormone are considered orexigenic hormones because they stimulate hunger. Leptin, on the other hand, is an anorexigenic hormone because it promotes feelings of fullness and reduces hunger. When ghrelin binds to receptors in the hypothalamus (a key region of the brain involved in appetite regulation) it increases the expression of neuropeptide Y (NPY) in neurons, which subsequently activates the mesolimbic reward center and makes us more “motivated” to eat.⁶ Shortly after we start eating food, anorexigenic peptides such as leptin and cholecystokinin (CCK) secrete satiety signals that communicate to the brain that we are getting full. This is why doctors and health experts will often say you should eat slowly; by doing so, you allow your gut and brain time to transmit the necessary signals to one another and control your food intake.

What is Adiponectin?

Similar to leptin, adiponectin is a peptide hormone secreted by adipose tissue that has distinct beneficial effects on metabolic function and weight loss. For starters, adiponectin works to downregulate glucose production in the liver and simultaneously increase fatty acid oxidation.⁷ (This is somewhat similar to what happens when you follow the ketogenic diet.) Moreover, there is an inverse association between adiponectin levels and body fat (i.e. individuals with lower adiponectin levels have a higher body fat percentage and vice versa). The health ramifications of chronic reduced adiponectin levels may include the development of  type-2 diabetes (insulin resistance) and atherosclerosis, among others.⁸ A study conducted by Beulens et. al in 2007 analyzed adiponectin levels and insulin sensitivity in 19 male subjects, 11 of whom were “lean”; the other 8 subjects were considered “overweight” by BMI standards.⁹ Those in the healthy weight group had roughly 20% higher total adiponectin levels and much higher insulin sensitivity than those in the overweight group. Moreover, high-molecular-weight (HMW) adiponectin was nearly 60% higher in individuals in the healthy weight group. Further evidence suggests that there’s a specific difference between the respective oligomers of adiponectin and their role in preventing metabolic abnormalities.¹⁰ It’s not surprising then that studies consistently find those with low levels of HMW adiponectin are more prone to metabolic syndrome.¹¹ One of the more curious findings of the Beulens et. al study was that changes in adiponectin levels didn’t appear to be associated with insulin sensitivity, but rather with intramuscular triglyceride (IMTG) content. This could signify a potential mechanism for how HMW adiponectin reduces the risk of metabolic diseases since high IMTG content is correlated with insulin resistance.¹² The ramifications of leptin resistance and low adiponectin levels should be quite clear by now. The correlation of these conditions to obesity, type-2 diabetes, and metabolic syndrome is no coincidence either. While the most obvious approach for losing weight is proper diet and exercise, certain dietary supplements may be useful adjuncts for establishing and maintaining healthy leptin and adipokine levels.

Supplements that Modulate Leptin, Ghrelin, and Adiponectin

Coenzyme Q10 (Ubiquinol)

Coenzyme Q10 (CoQ10) is an important intermediate in the electron transport chain that occurs in mitochondria. The electron transport chain is an integral component of ATP synthesis, and lacking CoQ10 can lead to excessive oxidative stress since it helps neutralize free radicals that result from electrons leaking out of the electron transport chain. Free radicals are reactive chemicals that contain unpaired electrons, such as superoxide and hydrogen peroxide. These molecules are highly unstable due to their electron configuration, meaning they readily react with nearby stable molecules and steal an electron in the process. This process is known as oxidation and it’s a normal part of our biology. However, having an excessive amount of free radicals in the body without sufficient antioxidant capacity can create chronic oxidative stress, which is the putative cause of a myriad of health conditions, including hypertension, cancer, organ failure, diabetes, and much more.¹³ Consequently, oxidative stress can exacerbate the ramifications of having low adiponectin and/or leptin resistance. This is where CoQ10 comes into play as ubiquinol is a powerful antioxidant that neutralizes free radicals that develop as part of the electron transport chain. Only small amounts of CoQ10 are found in the diet, and research suggests that our natural levels of CoQ10 drop significantly as we age.¹⁴  As such, it becomes increasingly important to supplement with CoQ10 (preferably ubiquinol instead of ubiquinone) as you grow older.

ALCAR (Acetyl-L-Carnitine)

ALCAR is a modified (acetylated) form of L-carnitine, a molecule that your body uses to transport fats across the mitochondrial membrane so they can be utilized for energy. A recent murine study found that ALCAR was effective for treating both insulin resistance and leptin resistance and even helped increase metabolic rate and reduce body fat after just one month.¹⁵ For weight loss purposes, an ALCAR supplement is essential and exceptionally safe since it’s not a stimulant.

Caralluma Fimbriata Whole Plant Extract

Caralluma fimbriata is an edible cactus indigenous to regions of western Asia. This particular cactus has been shown to improve appetite regulation in humans by blocking hunger signals of the hypothalamus.¹⁶ In fact, a recent meta-analysis concluded that overweight adults may benefit by using a Caralluma fimbriata supplement since it has been shown to decrease waist circumference and body weight in several studies.¹⁷

Cayenne Pepper Extract (Capsaicin)

Did you know that spicy kick to your tastebuds after eating hot peppers comes from compounds called capsaicinoids? Interestingly, capsaicinoids (specifically, capsaicin) quite literally help burn body fat, which is ironic given they also do a heck of a job “burning” a pepper lover’s mouth. Several studies have shown that adults who take a cayenne pepper extract supplement (a rich source of capsaicin) experience an increase in energy expenditure and a simultaneous decrease in their respiratory quotient, which positively impacts weight loss and appetite.¹⁸

Pyrroloquinoline quinone (PQQ)

PQQ is a redox cofactor that helps stimulate growth in bacteria and as a component of quinoproteins, which are a group of biologically important enzymes. In nature, PQQ is generally found in human breast milk, kiwi, and soils, but commercially it is produced from fermented soybeans. PQQ is an intriguing up-and-coming weight loss supplement since it has been shown to increase metabolic rate by activating mitochondrial biogenesis - the process by which cells create new mitochondria.¹⁹ In this regard, PQQ is somewhat similar CoQ10 in that it is beneficial for mitochondria and cellular energy production. Furthermore, PQQ appears to act as a cellular messenger that mimics some of the most basic physiological responses to exercise and increases the body’s production of irisin - the “exercise hormone”.²⁰ In humans, irisin is secreted in response to physical activity (particularly vigorous exercise) and research has shown that individuals with higher levels of irisin also have lower levels of ghrelin and higher levels of adiponectin, in addition to being leaner overall.²¹ In other words, PQQ can help alter adipokine levels in a manner that encourages body fat reduction and greater metabolic expenditure. It’s important to note that PQQ supplements tend to work best when taken at a dose of 20-30 mg per day and used in conjunction with a proper exercise regimen, like with most any weight loss supplement.

Apple Cider Vinegar

Research indicates that apple cider vinegar - which provides a diluted dose of acetic acid - slows gastric emptying, thereby helping reducing food intake when taken prior to a meal.²²  In turn, using an apple cider vinegar supplement is a great way to control your hunger and encourage weight loss. Furthermore, taking apple cider vinegar before a meal that’s rich in carbs can help reduce blood glucose spikes by as much as 30%, meaning ACV is especially useful for those with type-2 diabetes.²³

References

1. Lean, M. E. J. (1989). Brown adipose tissue in humans. Proceedings of the Nutrition Society, 48(2), 243-257.
2. Hebebrand, J, Td Muller, K Holtkamp, and B Herpertz-Dahlmann. The role of leptin in anorexia nervosa: clinical implications. Molecular Psychiatry aop.current (2003): 1409-1421. Print.
3. Jéquier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002 Jun; 967:379-88. Review.
4. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature402 (6762): 656–60.
5. Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH (2010). Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol.31 (1): 44–60.
6. Hewson AK, Dickson SL (2000). Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol.12 (11): 1047–1049.
7. Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev. 2005 Feb;6(1):13-21. Review.
8. Spranger, J., Kroke, A., Möhlig, M., Bergmann, M. M., Ristow, M., Boeing, H., & Pfeiffer, A. F. (2003). Adiponectin and protection against type 2 diabetes mellitus. The Lancet, 361(9353), 226-228.
9. Beulens, J. W., van Loon, L. J., Kok, F. J., Pelsers, M., Bobbert, T., Spranger, J., … & Hendriks, H. F. (2007). The effect of moderate alcohol consumption on adiponectin oligomers and muscle oxidative capacity: a human intervention study. Diabetologia, 50(7), 1388-1392.
10. Hara K, Horikoshi M, Yamauchi T et al. (2006). Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care, 29:1357–1362
11. Eglit, T., Lember, M., Ringmets, I., & Rajasalu, T. (2013). Gender differences in serum high-molecular-weight adiponectin levels in metabolic syndrome. European Journal of Endocrinology, 168(3), 385-391.
12. Hegarty, B. D., Furler, S. M., Ye, J., Cooney, G. J., & Kraegen, E. W. (2003). The role of intramuscular lipid in insulin resistance. Acta physiologica Scandinavica, 178(4), 373-383.
13. Aruoma, O. I. (1998). Free radicals, oxidative stress, and antioxidants in human health and disease. Journal of the American oil chemists' society, 75(2), 199-212.
14. Quinzii, C. M., & Hirano, M. (2011). Primary and secondary CoQ10 deficiencies in humans. Biofactors, 37(5), 361-365.
15. Iossa, S., Mollica, M. P., Lionetti, L., Crescenzo, R., Botta, M., Barletta, A., & Liverini, G. (2002). Acetyl-L-carnitine supplementation differently influences nutrient partitioning, serum leptin concentration and skeletal muscle mitochondrial respiration in young and old rats. The Journal of nutrition, 132(4), 636-642.
16. Griggs, J. L., Su, X. Q., & Mathai, M. L. (2015). Caralluma Fimbriata Supplementation Improves the Appetite Behavior of Children and Adolescents with Prader-Willi Syndrome. North American journal of medical sciences, 7(11), 509-16.
17. Astell, K. J., Mathai, M. L., & Su, X. Q. (2013). Plant extracts with appetite suppressing properties for body weight control: a systematic review of double-blind randomized controlled clinical trials. Complementary therapies in medicine, 21(4), 407-416.
18. Lejeune, M. P., Kovacs, E. M., & Westerterp-Plantenga, M. S. (2003). Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. British Journal of Nutrition, 90(3), 651-659.
19. Harris, C. B., Chowanadisai, W., Mishchuk, D. O., Satre, M. A., Slupsky, C. M., & Rucker, R. B. (2013). Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. The Journal of nutritional biochemistry, 24(12), 2076-2084.
20. Pekkala, S., Wiklund, P. K., Hulmi, J. J., Ahtiainen, J. P., Horttanainen, M., Pöllänen, E., ... & Alén, M. (2013). Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health?. The Journal of physiology, 591(21), 5393-5400.
21. Choi, Y. K., Kim, M. K., Bae, K. H., Seo, H. A., Jeong, J. Y., Lee, W. K., ... & Park, K. G. (2013). Serum irisin levels in new-onset type 2 diabetes. Diabetes research and clinical practice, 100(1), 96-101.
22. Hlebowicz, J., Darwiche, G., Björgell, O., & Almér, L. O. (2007). Effect of apple cider vinegar on delayed gastric emptying in patients with type 1 diabetes mellitus: a pilot study. BMC gastroenterology, 7(1), 46.
23. Chen, H., Chen, T., Giudici, P., & Chen, F. (2016). Vinegar functions on health: Constituents, sources, and formation mechanisms. Comprehensive Reviews in Food Science and Food Safety, 15(6), 1124-1138.