Hormone Biomarkers: Leptin

Optimal Takeaways

Leptin is a hormone with extensive effects on the body, including regulation of metabolism, appetite, weight, immunity, and inflammation. Leptin balance is crucial as lower levels are associated with malnourishment and increased susceptibility to infection. However, higher levels are associated with insulin resistance, metabolic syndrome, overfeeding, obesity, inflammation, and increased cardiovascular risk.

Standard Range:

Male: 0.30 - 13.40 ng/mL (0.30 - 13.40 ug/L)

Female: 4.70 - 23.70 ng/mL (4.70 - 23.70 ug/L)

The ODX Range:

Male: 1.20 - 3.9 ng/mL (1.20 - 3.90 ug/L)      

Female: 4.70 - 11.00 ng/mL (4.70 - 11.00 ug/L) 

Low leptin may be associated with genetic factors, malnourishment, reduced body fat mass (Gropper 2021), increased susceptibility to infection (Perez-Perez 2020), and leptin deficiency associated with obesity and hyperphagia during childhood (Izquierdo 2019).

High leptin can be seen with overfeeding, excess adipose tissue, obesity (Gropper 2021), leptin resistance (Izquierdo 2019), insulin resistance, metabolic syndrome, diabetes (Ghadge 2019), inflammation, parasitic infection (Perez-Perez 2020), compromised vascular integrity, hypertension, atherosclerosis (Dudeck 2020), and increased risk of CHF, acute coronary syndrome, MACE, and cardiac death in those with established coronary artery disease (Puurunen 2017).

Overview

Leptin is a hormone secreted by white adipose tissue. Blood levels correlate with body fat and increase as adipose tissue increases. Leptin affects energy homeostasis by decreasing appetite and increasing energy expenditure, creating a negative energy balance. Leptin impacts glucose and lipid metabolism via its effects on the liver, pancreas, skeletal muscle, and adipose tissue. Ultimately, leptin promotes fatty acid oxidation for energy use, inhibits insulin synthesis and secretion, and suppresses insulin signaling in the liver and white and brown adipose tissue. Although circulating levels may be normal or elevated in obesity, the obese appear resistant to leptin (Gropper 2021).

Circulating leptin must cross the blood-brain barrier (BBB) to exert its anorexigenic effects on the hypothalamus. Obesity may lead to saturation of BBB transporters, leptin resistance, and compromised regulation of appetite and body weight, despite elevated levels in the blood (Izquierdo 2019). However, leptin is also produced in the anterior pituitary gland and helps regulate the hypothalamus-pituitary-adrenal axis, the hypothalamus-pituitary-thyroid axis, and the hypothalamus-pituitary-gonadal axis (Lloyd 2001, Roubos 2012). The balance and effects of circulating versus locally produced leptin in the brain are complex and continue to be investigated.

Leptin is produced to some extent in the stomach and skeletal muscle and, as a cytokine hormone, has effects beyond weight maintenance, basal metabolism, and thermogenesis. It profoundly affects the immune system, hematopoiesis, reproduction, and immunity. Leptin acts as a pro-inflammatory cytokine in the immune system, and research suggests that increased peripheral production of leptin may be associated with autoimmune and chronic inflammatory disorders (Procaccini 2012). The presence of chronic inflammation from autoimmunity, infectious disease, or dysbiosis may inhibit leptin, contributing to a vicious cycle of inflammation and dysfunction (Perez-Perez 2020).

Elevated leptin may be a marker for an increased risk of insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease due to its direct correlation with obesity and pro-inflammatory adipose tissue (Ghadge 2019). One population-based study, noting that the risk of insulin resistance and metabolic syndrome increases with increasing leptin, recommended cut-off levels of 3.6-4.1 ng/mL for men and 11.0 ng/mL for women to identify an increased risk of cardiometabolic disease (Esteghamati 2011). Leptin was used as a marker of adiposity in 89 females with rheumatoid arthritis, with elevated levels correlating with increased body fat percentage. Researchers recommend a leptin cut-off of 10.3 ng/dL for identifying adiposity (Guimaraes 2018).

Elevated leptin levels have been associated with atherosclerosis, myocardial infarction, stroke, and increased markers of inflammation such as CRP. The risk of cardiovascular disease is significantly increased when both leptin and CRP are elevated. Research suggests that leptin may stimulate CRP production in the liver, while CRP may reduce leptin’s ability to bind to cell receptors effectively (Hribal 2014).

In patients with established coronary artery disease, elevated leptin was independently associated with an increased risk of major adverse cardiac events, acute coronary syndrome (ACS), and stroke. Researchers recommended general cut-offs for leptin of 9.9 ng/mL or greater for ACS or stroke and 14.1 ng/mL or greater for MACE (Puurunen 2017).

In one study of hypogonadal men, 12 months of testosterone therapy improved metabolic health and significantly reduced serum leptin from a mean of 6.2 ng/mL to 4.0 ng/mL. Treatment also significantly reduced hs-CRP, BMI, and body fat mass and significantly increased adiponectin (Dudek 2020).

References

Cundrle, Ivan Jr et al. “Low leptin concentration may identify heart failure patients with central sleep apnea.” Journal of sleep research vol. 27,2 (2018): 240-243. doi:10.1111/jsr.12574

Dudek, Piotr et al. “The effects of testosterone replacement therapy in men with age-dependent hypogonadism on body composition, and serum levels of leptin, adiponectin, and C-reactive protein.” Endokrynologia Polska vol. 71,5 (2020): 382-387. doi:10.5603/EP.a2020.0048

Esteghamati, Alireza et al. “Leptin cut-off values for determination of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007).” Endocrine vol. 40,1 (2011): 117-23. doi:10.1007/s12020-011-9447-4

Ghadge, Abhijit A, and Amrita A Khaire. “Leptin as a predictive marker for metabolic syndrome.” Cytokine vol. 121 (2019): 154735. doi:10.1016/j.cyto.2019.154735

Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8th edition. Wadsworth Publishing Co Inc. 2021.

Guimaraes, Maria Fernanda Brandão de Resende et al. “Leptin as an obesity marker in rheumatoid arthritis.” Rheumatology international vol. 38,9 (2018): 1671-1677. doi:10.1007/s00296-018-4082-5

Hribal, Marta Letizia et al. “Role of C reactive protein (CRP) in leptin resistance.” Current pharmaceutical design vol. 20,4 (2014): 609-15. doi:10.2174/13816128113199990016

Izquierdo, Andrea G et al. “Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later?.” Nutrients vol. 11,11 2704. 8 Nov. 2019, doi:10.3390/nu11112704

Lloyd, R V et al. “Leptin and leptin receptor in anterior pituitary function.” Pituitary vol. 4,1-2 (2001): 33-47. doi:10.1023/a:1012982626401  

Perez-Perez, Antonio et al. “Role of Leptin in Inflammation and Vice Versa.” International journal of molecular sciences vol. 21,16 5887. 16 Aug. 2020, doi:10.3390/ijms21165887

Procaccini, Claudio et al. “Leptin as an immunomodulator.” Molecular aspects of medicine vol. 33,1 (2012): 35-45. doi:10.1016/j.mam.2011.10.012

Puurunen, Veli-Pekka et al. “Leptin predicts short-term major adverse cardiac events in patients with coronary artery disease.” Annals of medicine vol. 49,5 (2017): 448-454. doi:10.1080/07853890.2017.1301678

Roubos, Eric W et al. “Leptin and the hypothalamo-pituitary-adrenal stress axis.” General and comparative endocrinology vol. 177,1 (2012): 28-36. doi:10.1016/j.ygcen.2012.01.009