Ten years of leptin replacement therapy

Abstract

SummaryLeptin is a pleiotropic cytokine-like hormone that is involved in the regulation of energy intake and expenditure, neuroendocrine function, immunity and lipid and glucose metabolism. The few humans with genetically based leptin deficiency provide a unique model to assess those effects. We have identified five Turkish patients (one male and two female adults; one boy and one girl) with congenital leptin deficiency due to a missense mutation in the leptin gene. Four of these patients were treated with physiological doses of recombinant methionyl human leptin. Body composition, brain structure and function, behaviour, immunity and endocrine and metabolic parameters were evaluated before and during treatment. Our results showed that leptin has peripheral, hypothalamic and extra-hypothalamic effects. Within the endocrine system, leptin regulates the circadian rhythms of cortisol, thyroidstimulating hormone, luteinizing hormone and follicle-stimulating hormone. In the brain, leptin controls energy balance and body weight, and plays a role on neurogenesis and brain function. Leptin is a key element of the adiposinsular axis, enhances immune response, and regulates inflammation, coagulation, fibrinolysis and platelet aggregation. Our 10-year experience in treating these unique patients provided valuable data on the peripheral and central effects of leptin. Those results can be taken into account for the development of leptin-based therapies for other diseases.

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

“…Leptin levels are directly correlated with fat mass and are elevated in obese patients, who are also leptin resistant. Leptin deficient mice and humans are severely obese and have several metabolic and endocrine altera tions, such as hyperglycemia, insulin resistance, hyper triglyceridemia, hypogonadotropic hypogonadism, and central hypothyroidism (6,7).…”

Insensitivity of well-conditioned mature sheep to central administration of a leptin receptor antagonist

“…These adaptations are reversed by leptin therapy, confirming their leptin dependence (Leibel, 2008;Paz-Filho et al, 2011). In sheep and other ruminants, animals lacking leptin have not been identified and leptin actions have been inferred by exogenous leptin administration of animals fed once daily an Ewes (n = 5) received intracerebroverticular infusion of artificial cerebrospinal fluid (aCSF), ovine leptin (4 µg/h; L) or the combination of both ovine leptin and ovine leptin antagonist (4 and 40 µg/h, respectively; L + OLA) over a 2-day period.…”

“…In humans and rodents, a lack of leptin triggers CNS-driven adaptations such as increased appetite, higher metabolic efficiency and peripheral insulin resistance (Leibel, 2008;Farooqi and O'Rahilly, 2009;Paz-Filho et al, 2011). These adaptations are reversed by leptin therapy, confirming their leptin dependence (Leibel, 2008;Paz-Filho et al, 2011).…”

“…These adaptations were initially attributed to hormone actions in the periphery (Bauman and Currie, 1980), but it is now clear that insufficient leptin contributes by targeting the CNS (Myers and Olson, 2012). These adaptive responses were identified by studying mice and humans suffering from a total leptin deficiency (Leibel, 2008;Paz-Filho et al, 2011) and include increased appetite, higher metabolic efficiency and peripheral insulin resistance (Leibel, 2008;Farooqi and O'Rahilly, 2009;Paz-Filho et al, 2011). In contrast, the role of leptin in sheep has been explored exclusively via exogenous leptin administration to animals endowed with a completely intact leptin system.…”

Molecular Psychiatry: 20 Years

“…These include inflammatory mediators and adipokines, [20][21][22][23] as well as the microbiome. 24,25 One exciting feature of our twentieth anniversary, and hopefully of our next 20 years, is our partnership with the American Journal of Psychiatry in hosting a joint symposium at the Annual Meeting of the American Psychiatric Association in Toronto, Ontario, Canada.…”