A Summary on Leptin Resistance
My involvement in the weight loss industry in fitness and with Diet Achiever app has me very interested in leptin resistance. Indeed, this is an issue that many obese people face, and it has been a subject of intensive research in the area of bodyweight regulation. Leptin is a powerful hormone secreted by adipose cells to regulate energy intake and bodyweight regulation (Mercola, 2012). Mechanisms of action include decreasing appetite, increasing the metabolic rate, inhibiting fat gain, and increasing physical activity (UNH, 2017). Leptin stimulates hypothalamic neurons containing various neuropeptides to stimulate or inhibit eating to maintain homeostasis of body weight. After release by the adipose tissue leptin signals information to the brain (by crossing the blood brain barrier (BBB) and cerebral spinal fluid (CSF)) about the status of the body energy stores (Klok, Jakobsdottir, & Drent, 2007). Leptin suppresses the mechanisms designed to increase bodyfat and activates mechanisms to decrease it. This results in a decrease in food intake and an increase in energy expenditure to maintain the size of the body fat stores (Klok et al., 2007). Leptin is also produced by the stomach, which is thought to control meal size in tandem with other satiety peptides (Klok et al., 2007). Additionally, gastric leptin secretion is stimulated by the administration of insulin, inferring carbohydrates can increase leptin levels. Leptin has other physiological functions as well. These include “reproductive competence and immune function and contributes to the regulation of metabolic homeostasis (by modulating insulin secretion, hepatic glucose production, and lipid metabolism), as well as some aspects of bone biology” (Myers et al., 2012).
Leptin Resistance Defined
Leptin resistance is defined by Myers et. al, as the “failure of endogenous or exogenous leptin to promote anticipated salutary metabolic outcomes in states of over-nutrition or obesity, although the hormone’s inability to promote desired responses in specific situations results from multiple molecular, neural, behavioral, and environmental mechanisms” (Myers et al., 2012). What is important to point out is that “leptin resistance” does not infer there is a single mechanism, but rather that the condition in multifactorial. The term leptin resistance arose when researchers discovered that serum and plasma leptin levels are higher with subjects with a higher BMI and higher total bodyfat percentage. Despite the fact that people with obesity demonstrate elevated leptin levels, due to higher adipose tissues, the brain is not responding appropriately. Therefore, the brain instructs the body to respond as if leptin levels are low by increasing eating, decreasing metabolic rate, and increasing fat storage (UMH, 2017). It is hypothesized that the leptin either is unable to cross the BBB, or the brain is insensitive to it. “In essence, the brain thinks the body is starving even though it is not” (UMH, 2017). This leads to a viscous cycle of additional weight gain, insulin resistance, hyperlipidemia, diabetes and CV disease. This makes losing weight even more challenging, especially since leptin resistance is associated with a new homeostatic set point weight, characterized by a higher body fat %, higher leptin levels and higher food intake. If fat is lost, the brain will ramp up hunger and the desire to eat, reducing energy expenditure, and even reducing levels of thyroid hormone.
The causes of leptin resistance are sometimes conflicting and still up for debate. A general consensus indicates that the development of leptin resistance follows a similar etiology as insulin resistance. Leptin resistance most likely involves a period of over-eating that triggers a defect in the leptin system. It exposes the hypothalamus to abnormally high leptin levels that may damage the hypothalamus, making the hypothalamus less sensitive to leptin, and a sustained increase in leptin levels. Studies demonstrate that humans develop leptin resistance because overfeeding (Klok et al., 2007). The central nervous system mediates most of leptin’s actions, including control of neuroendocrine axes, the ANS, satiety, the limbic system and other behaviors (Myers et al., 2012).
Other possible causes of leptin resistance include:
- Defective leptin transport across BBB– The capacity of leptin transporter is lower in obese individuals, appearing to be an acquired defect associated with the development of obesity (Myers et al., 2012)
- Changes in circulating leptin binding proteins-often triggered by gluten. Digested wheat gluten can inhibit the binding of leptin to leptin receptors, which are often improved when bread is replaced with vegetables in otherwise similar low-calorie diets (Jonsson et al., 2015)
- Diminished LEP-B signaling due to inflammation or feedback inhibition (Myers et al., 2012)
- Alterations in the development of leptin-regulated neurons and other components of the circuitry that controls leptin action could also blunt leptin action throughout life.
- Inflammation in the hypothalamus caused by diets high in processed sugar and saturated fat. Thaler et. al (2012). (Myers et al., 2012) indicated that studies conducted on rats susceptible to diet induced obesity demonstrated neuronal injury in parts of the brain critical for energy homeostasis after a high fat diet. This was evidenced by gliosis in the hypothalamus of MRI images of obese humans.
- Leaky gut as it contributes to neuroinflammation and leaky brain BBB. Gluten is also a big culprit here as it can increase gut permeability and contribute to overall systemic inflammation and neuroinflammation (UNH, 2017).
What can you do about it?
According to Meyers et al (2012), rather than addressing leptin resistance, defining behavioral and metabolic sensitivity to leptin may be more practical. “A pragmatic approach to leptin resistance and therapeutic leptin action thus focuses not on defining clinical leptin resistance in a universal manner, but rather on assessing leptin sensitivity: Which individuals are likely to respond to leptin and/or can be sensitized to exogenous leptin?” (Myers et al., 2012)
Lifestyle strategies- there are some dietary strategies to increase leptin sensitivity based on the mechanisms involved in leptin resistance
- Gluten free diet– as mentioned earlier, since gluten can bind the leptin receptors, going gluten free is a good strategy. Also, gluten is strongly linked to intestinal permeability that can cause inflammation in the hypothalamus, reducing leptin sensitivity. Removing gluten from the diet will help heal leaky gut, improve gut barrier function and reduce inflammation systemically, particularly the brain.
- High fiber, prebiotic based diet– Fiber not only provides satiety, it also promotes the proliferation of good bacteria in the gut. Prebiotics are found in food such as garlic, onions, leeks, Jerusalem artichokes, shallots, cabbage, most fruits, and some nuts.
- Probiotics– some probiotics have been demonstrated to improve leptin resistance, such as numerous strains of lactobacillus and saccharomyces boulardii. The results of a study in 2017 demonstrated that serum concentrations of leptin, insulin, and HOMA-IR decreased significant in the probiotic (and prebiotic) group compared to placebo (Behrouz, Jazayeri, Aryaeian, Zahedi, & Hosseini, 2017).
- Polyphenols– Polyphenols have strong anti-inflammatory properties. Many phytochemicals can directly reduce inflammation within the brain and systemically, with polyphenols standing out the most. Polyphenols that can directly decrease inflammation in the hypothalamus include: curcumin, anthocyanins (found in blueberries, plums), resveratrol, and catechins (found in green tea).
- Exercise- Physical activity can have direct anti-inflammatory actions on the hypothalamus that may be able restore leptin sensitivity(Yi et al., 2012) . The stress from exercise can secrete IL-6 which can enter the brain and paradoxically can have anti-inflammatory effects that can improve leptin sensitivity.
Supplements are often controversial in weight loss, but I found two that could be promising:
- Irvingia gabonensis- A study in 2008 demonstrated that Irvingia gabonensis seed extract (IGOB131) can influence multiple mechanisms in managing obesity such as influencing PPAR gamma, leptin, and adiponectin gene expressions (Oben, Ngondi, & Blum, 2008). I would like to see more research on the efficacy of this supplement, the ones I found were scarce.
- Spore based probiotics-There is some evidence that spore-based probiotics are associated with a reduction in inflammatory biomarkers which may exert beneficial benefits by altering the gut microbiome, intestinal permeability or a combination of these two effects (McFarlin, Henning, Bowman, Gary, & Carbajal, 2017). There was as 42% reduction in metabolic endotoxemia after 30-day supplementation of spore-based probiotics. A significant reduction in inflammatory cytokines (IL-1B, IL-6, IL-8 and MCP-1) which are released by adipose tissues, were also observed. It can be inferred that the improvements in these inflammatory biomarkers can lead to improved leptin resistance and could be used as an adjunctive to dietary interventions aimed to reduce bodyweight.
Behrouz, V., Jazayeri, S., Aryaeian, N., Zahedi, M. J., & Hosseini, F. (2017). Effects of Probiotic and Prebiotic Supplementation on Leptin, Adiponectin, and Glycemic Parameters in Non-alcoholic Fatty Liver Disease: A Randomized Clinical Trial. Middle East J Dig Dis, 9(3), 150-157. doi:10.15171/mejdd.2017.66
Jonsson, T., Memon, A. A., Sundquist, K., Sundquist, J., Olsson, S., Nalla, A., . . . Linse, S. (2015). Digested wheat gluten inhibits binding between leptin and its receptor. BMC Biochem, 16, 3. doi:10.1186/s12858-015-0032-y
Klok, M. D., Jakobsdottir, S., & Drent, M. L. (2007). The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev, 8(1), 21-34. doi:10.1111/j.1467-789X.2006.00270.x
McFarlin, B. K., Henning, A. L., Bowman, E. M., Gary, M. A., & Carbajal, K. M. (2017). Oral spore-based probiotic supplementation was associated with reduced incidence of post-prandial dietary endotoxin, triglycerides, and disease risk biomarkers. World J Gastrointest Pathophysiol, 8(3), 117-126. doi:10.4291/wjgp.v8.i3.117
Myers, M. G., Jr., Heymsfield, S. B., Haft, C., Kahn, B. B., Laughlin, M., Leibel, R. L., . . . Yanovski, J. A. (2012). Challenges and opportunities of defining clinical leptin resistance. Cell Metab, 15(2), 150-156. doi:10.1016/j.cmet.2012.01.002
Oben, J. E., Ngondi, J. L., & Blum, K. (2008). Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene. Lipids Health Dis, 7, 44. doi:10.1186/1476-511x-7-44
Yi, C. X., Al-Massadi, O., Donelan, E., Lehti, M., Weber, J., Ress, C., . . . Hofmann, S. M. (2012). Exercise protects against high-fat diet-induced hypothalamic inflammation. Physiol Behav, 106(4), 485-490. doi:10.1016/j.physbeh.2012.03.021