Leptin in Healthy Humans
A primary hormone from adipose tissue, leptin was discovered in 1994. It was identified as a satiety signal that controls energy balance and metabolism. In healthy persons, leptin tells the brain to stimulate the thyroid gland to produce a normal metabolic rate. However, in obesity, the system is altered. In fact, increased leptin, leading to leptin resistance, is a well-established endocrine change in obesity.[1] First let’s look at leptin function in healthy humans.
Leptin brings the “I’m full” message to the brain. As fat stores rise, leptin rises, telling the brain in a louder and louder voice that we have eaten enough and to stop eating. Hence, it is a satiety hormone. It also says to the brain: we have lots of fat stores so speed up metabolism and get rid of some of them! This effect is via stimulation of thyroid function.
Studies by Ghizzoni, et al. revealed that, under baseline physiological conditions, leptin promotes a healthy metabolic rate by stimulating the hypothalamic-pituitary-thyroid (HPT) axis.[2] Roef, et al. has indeed demonstrated positive associations between leptin, fT3 and fT4 in healthy, euthyroid men.[3] Perello and colleagues were able to pinpoint its action: leptin increases thyrotropin-releasing hormone (TRH) directly in the paraventricular nucleus (PVN) of the hypothalamus.[4]
If we look at it from an evolutionary perspective, we see that a primary purpose of leptin is to coordinate the metabolic, endocrine and behavioral responses to starvation. In starvation or energy deficit conditions, fat is broken down for fuel. Leptin levels therefore, drop. TRH is then absent its normal stimulation from leptin. Metabolism consequently slows down and conserves stored energy. When food is available, we begin to fill up fat stores again. In response, leptin levels go up and bring the message “I’m full. Stop eating & increase metabolism now.”
Leptin and Weight
But what about cases where leptin is elevated? Overweight patients in one study, compared to controls, were found to have lower fT3, fT4, a higher prevalence of poor thyroid function and often presented with higher anti-thyroid antibodies.[5] Correlation analysis in this study demonstrated leptin levels positively associated with poor thyroid health.
Subsequent studies have validated these findings. Duntas and Micic, for example, showed that excess belly fat, by raising leptin above normal, raises TSH secretion, and thereby can trigger thyroid issues.[6] To summarize, elevated weight leads to increased leptin which can impair thyroid function.
However, there is another, perhaps more insidious complication resulting from increases in weight. Most overweight humans and rodents, as well, have high levels of plasma leptin, which neither reduce appetite nor increase energy expenditure. The absence of leptin’s positive effects in obese, hyperleptinemic states is known to be due to the development of leptin resistance.[7]
Whenever a hormone is chronically high, some of its receptors will down-regulate. Once leptin resistance has set in, we could expect less-than-normal stimulation of the HPT axis and thus lower thyroid function. In rat models, it has been shown that increases in weight (and even short-term over-feeding) increase leptin resistance and that calorie restriction does the opposite, increasing leptin receptor sensitivity.[8],[9] Weight loss and calorie restriction, then, would be efficacious in cases where individuals are overweight, have leptin resistance, and poor thyroid function.
Influences on Leptin
The production of leptin by white fat is subject to a number of regulatory influences, including insulin and glucocorticoids (which are stimulatory), and fasting and beta-adrenoceptor agonists (which are inhibitory).[10] For instance, it is clear that insulin will stimulate leptin secretion from adipose tissue.[11] The downstream results contribute to further leptin resistance, less TSH stimulation and lower thyroid function. CRP, a marker for systemic inflammation, has also been shown to contribute to leptin resistance.[12] This is a vicious circle, as the lower thyroid function can contribute to weight gain, more leptin resistance, etc.
Interventions to Restore Leptin Action
Dietary considerations include a whole-foods cuisine with an emphasis on protein and good fats, rather than insulin-inducing carbohydrates. Since leptin resistance and insulin resistance go hand-in-hand, blood sugar swings must be avoided. Weight loss and calorie restriction will help decrease leptin resistance, as does fasting.[13]
Exercise has also been shown to restore leptin signaling at the hypothalamic level.[14],[15],[16] In rodent models, acetyl-L-carnitine was able to lower serum leptin in aged animals.[17] Recent rodent research has also shown efficacy for ginseng (Panax) in restoring effective leptin signaling in the hypothalamus of obese animals.[18] Given leptin’s relationship to CRP, lowering inflammation would also be necessary.
Therefore, to achieve leptin sensitivity and thereby restore thyroid balance, it is recommended to lose weight, balance blood sugar, reduce inflammation, practice calorie restriction (or even fasting) and engage in exercise! Haven’t we heard this before???
References
[1] Álvarez-Castro P, Sangiao-Alvarellos S, Brandón-Sandá I, et al. (2011). [Endocrine function in obesity]. Endocrinol Nutr. 2011 Oct;58(8):422-32.
[2] Ghizzoni L, Mastorakos G, Ziveri M, et al. (2001). Interactions of leptin and thyrotropin 24-hour secretory profiles in short normal children. J Clin Endocrinol Metab. May;86(5):2065-72.
[3] Roef G, Lapauw B, Goemaere S, et al. (2012). Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men. Eur J Endocrinol. Nov;167(5):719-26.
[4] Perello M, Cakir I, Cyr NE, et al. (2010). Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level. Am J Physiol Endocrinol Metab. Dec;299(6):E976-89.
[5] Marzullo P, Minocci A, Tagliaferri MA, et al. (2010). Investigations of thyroid hormones and antibodies in obesity: leptin levels are associated with thyroidautoimmunity independent of bioanthropometric, hormonal, and weight-related determinants. J Clin Endocrinol Metab. Aug;95(8):3965-72.
[6] Duntas L, Micic D. (2012). Adiposopathy and thyroid disease: tracing the pathway to cardiovascular risk. Expert Rev Cardiovasc Ther. Jun;10(6):797-803.
[7] Mantzoros CS, Ozata M, Negrao AB, et al. (2001). Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab. 2001 Jul;86(7):3284-91.
[8] Balaskó M, Soós S, Székely M, et al. (2014). Leptin and aging: Review and questions with particular emphasis on its role in the central regulation of energy balance. J Chem Neuroanat. Nov;61-62:248-55.
[9] Wang J, Obici S, Morgan K, et al. (2001). Overfeeding rapidly induces leptin and insulin resistance. Diabetes. Dec;50(12):2786-91.
[10] Trayhurn P, Hoggard N, Mercer JG, et al. (1999). Leptin: fundamental aspects. Int J Obes Relat Metab Disord. Feb;23 Suppl 1:22-8.
[11] Seufert J. (2004). Leptin effects on pancreatic beta-cell gene expression and function. Diabetes. Feb;53 Suppl 1:S152-8.
[12] Chen K, Li F, Li J, et al. (2006). Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med. Apr;12(4):425-32. Epub 2006 Apr 2.
[13] Palou M, Sánchez J, Rodríguez AM, et al. (2009). Induction of NPY/AgRP orexigenic peptide expression in rat hypothalamus is an early event in fasting: relationship with circulating leptin, insulin and glucose. Cell Physiol Biochem. 23(1-3):115-24.
[14] Chiarreotto-Ropelle EC, Pauli LS, Katashima CK, et al. (2013). Acute exercise suppresses hypothalamic PTP1B protein level and improves insulin and leptin signaling in obese rats. Am J Physiol Endocrinol Metab. Sep 1;305(5):E649-59.
[15] Koga S, Kojima A, Ishikawa C, et al. (2014). Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression. Neurobiol Dis. Nov;71:180-92.
[16] Krawczewski Carhuatanta KA, Demuro G, Tschöp MH, et al. (2011). Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity. Endocrinology. Jul;152(7):2655-64.
[17] Iossa S, Mollica MP, Lionetti L, et al. (2002). Acetyl-L-carnitine supplementation differently influences nutrient partitioning, serum leptin concentration and skeletal muscle mitochondrial respiration in young and old rats. J Nutr. Apr;132(4):636-42.
[18] Wu Y, Yu Y, Szabo A, et al. (2014). Central inflammation and leptin resistance are attenuated by ginsenoside rb1 treatment in obese mice fed a high-fat diet. PLoS One. Mar 27;9(3):e92618.
