In a new study, Yale researchers offer insight into leptin, a hormone that plays a key role in appetite, overeating, and obesity.
Their findings advance knowledge about leptin and weight gain, and also suggest a potential strategy for developing future weight-loss treatments, they said.
The study, led by investigators at Yale and Harvard, was published the week of June 17, 2019, in the journal PNAS.
Leptin, which is secreted by fat cells, informs the brain when fuel stored in body fat and in the liver is becoming depleted.
It has not been well understood how low leptin concentrations in plasma – the largest component of blood – increase appetite.
The researchers studied the biology of leptin in rodents.
They also investigated the influence of nerve cells in the brain known as AgRP neurons, which regulate eating behavior.
The researchers discovered that the mechanisms by which reductions in plasma leptin concentrations stimulate food intake are not limited to the brain, as previously thought.
In rodents, fasting first activates leptin receptors in the brain, followed by an intermediary step that involves the endocrine system.
This system includes the pituitary and adrenal glands, which secrete another hormone, corticosterone, that regulates energy, stress responses, and food intake.
The research team learned that this chain of events is required for leptin to stimulate hunger when food is restricted, or when diabetes is poorly controlled and plasma leptin concentrations drop below a critical threshold, said Gerald Shulman, M.D., the George R. Cowgill Professor of Medicine at Yale School of Medicine, and co-corresponding author of the study.
In further experiments, the researchers also showed that plasma corticosterone activates AgRP neurons, which increases hunger when either leptin or blood-sugar levels are low, Shulman noted.
In humans, leptin and blood sugar drop when people diet.
These findings add to scientists’ knowledge of leptin, which has been the focus of research on obesity and weight loss since its discovery in the 1990s.
The study reveals “the basic biology of leptin, and how the endocrine system is mediating its effect to regulate food intake under conditions of starvation and poorly controlled diabetes,” said Shulman.
The research also lends support to a different strategy for developing drugs that treat obesity. “It suggests that AgRP neurons may be an attractive therapeutic target,” he said.
More than 20 years ago, leptin and its receptors were identified as key regulators of body weight and energy homeostasis.
A minor increase in leptin concentration reduces the appetite and leads to a decrease in body weight;3 however, in obesity, despite increased leptin concentration, the efficacy of the anorexic effect of leptin is decreased,1,3 with leptin resistance developing due to a defect in intracellular signaling associated with the leptin receptor or decreases in leptin transport across the blood–brain barrier (BBB).4
Clear criteria for defining leptin resistance and its diagnostic use have not been established. For in vivo studies, it is difficult to elucidate the molecular mechanisms underlying the development of leptin resistance.
The majority of studies examining the effects of leptin resistance on various metabolic processes are performed using mice with a defect in the Ob-P leptin-receptor gene.5
This mutation is rare in the human population, which complicates research on leptin resistance and identification of possible diagnostic markers.
Furthermore, when assessing leptin resistance, a number of questions should be answered, including whether the presence of high leptin concentration is sufficient to establish the diagnosis of leptin resistance, what threshold for the weakened response should be considered as leptin resistance, and whether leptin resistance should be defined according to a one-time increase in leptin concentration or to dynamic changes in the concentration over time.6,7
Research on the pleiotropic effects of leptin, including those involving the immune system, hemopoiesis, and angiogenesis, and the participation of leptin in the development of cardiovascular and autoimmune diseases and cancer, has renewed the interest in studying leptin, its receptors, and their possible diagnostic use.8
More information: Rachel J. Perry el al., “Leptin’s hunger-suppressing effects are mediated by the hypothalamic–pituitary–adrenocortical axis in rodents,” PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1901795116
Journal information: Proceedings of the National Academy of Sciences
Provided by Yale University