Leptin is a hormone produced primarily by adipose tissue. Its concentration in the bloodstream provides the brain with information about the availability of energy reserves. Based on this information, the brain not only regulates appetite and body weight but also coordinates metabolic responses in peripheral organs and tissues, including the liver, pancreas, and adipose tissue.
In people with obesity, leptin levels are usually elevated, yet the brain responds inadequately to its signal, a condition known as leptin resistance. An important question, however, remains unresolved: is this impairment merely a consequence of obesity, or can reduced leptin action in the brain contribute to the development of metabolic abnormalities before overt obesity develops?
To address this question, we reduced central leptin signaling in young adult, normal-weight rats with normal circulating leptin levels by administering a leptin antagonist directly into the brain in a controlled manner.
In our study published in The Journal of Physiology [1], we found that reduced leptin action in the brain rapidly altered feeding behavior. The animals increased their food intake, particularly during the phase of the day when they would normally consume less food, and showed moderate increases in body weight and visceral fat. However, the consequences extended well beyond changes in food intake or body weight.
The animals developed impaired glucose tolerance, elevated circulating insulin and glucagon concentrations, increased fat accumulation in the liver, and alterations in branched-chain amino acid metabolism. Changes were also observed in white and brown adipose tissue, as well as in mechanisms involved in energy utilization and storage. Taken together, these findings indicate that the animals developed a metabolic profile consistent with early metabolic dysfunction, despite the absence of severe obesity or exposure to a high-fat diet.
These findings support a broader view of leptin that extends beyond its well-established role in appetite regulation. Central leptin signaling appears to help the brain accurately interpret the availability of energy reserves and coordinate the function of multiple metabolic organs accordingly. When this communication is impaired, disturbances in glucose, lipid, and amino acid metabolism may emerge before substantial obesity develops.
Because this study was conducted in animals, its findings cannot be directly extrapolated to humans. Nevertheless, they raise an important possibility: some metabolic abnormalities may develop before excess body weight becomes apparent. A better understanding of how the brain senses and responds to energy reserves could help identify early stages of metabolic dysfunction and, in the future, contribute to preventive strategies that extend beyond body weight alone.
[1] Pintado, C., Mazuecos, L., Gómez-Torres, Ó., Merino, B., Casanueva-Álvarez, E., Rubio, B., Burgos-Ramos, E., Artigas-Jerónimo, S., Moltó, E., Ramos, I. M., Poveda, J. M., Perdomo, G., Cózar-Castellano, I., Arribas, C., Bernal-Mizrachi, E., Andrés, A., & Gallardo, N. (2026). Chronic attenuation of brain leptin signalling is associated with early metabolic dysfunction in lean rats. The Journal of physiology, 604(12), 4717–4744. https://doi.org/10.1113/JP290832
Professors of Biochemistry and Molecular Biology
Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha; Health Research Institute of Castilla-La Mancha (IDISCAM), Ciudad Real, Spain
Our group aims to understand how diminished or deficient brain leptin signaling in normal-weight, leptin-sensitive adult rats is associated with hypothalamic nucleus-specific alterations that induce changes in peripheral tissues, including the liver, pancreas, and adipose tissue, thereby mimicking the metabolic alterations associated with aging, including the development of insulin and leptin resistance. We also investigate whether central leptin deficiency is associated with hypothalamic nucleus-specific alterations in protein and lipid composition, as well as with microglial activation and proliferation and neuroinflammation.