Neurons Without Leptin Receptors Still Respond to the Hunger Hormone

Researchers from the Vanderbilt University School of Medicine Basic Sciences have uncovered the first example of activity-dependent development of hypothalamic neural circuitry. Although previous research has shown that the hormone leptin acts directly on hunger neurons through leptin receptors to promote the development of neural circuitry, results that will be published in PNAS on Nov. 25 indicate that certain neurons that do not express leptin receptors are nonetheless sensitive to its activity.

The research, led by the lab of Richard Simerly, Louise B. McGavock Professor and professor of molecular physiology and biophysics, also supports a novel role for leptin in specifying the development of neural circuits involved in autonomic regulation and food intake. His lab found that silencing the activity of hunger neurons (called “AgRP” neurons) during the critical, postnatal period of neuronal circuitry development may exert lasting effects on the structure and function of circuits that control energy balance.

Leptin is a hormone that, in adults, regulates hunger by providing a sensation of satiety and helps maintain body weight on a long-term basis. In the weeks following birth, however, leptin also helps direct the formation of circuits that control homeostatic functions.

In their PNAS paper, the Simerly lab describes three primary results:

1. Leptin is required for the normal development of neural connections between hypothalamic oxytocin neurons, which link AgRP neurons with brainstem neurons that coordinate autonomic responses associated with feeding, even though oxytocin neurons in this pathway do not express leptin receptors.
2. The development of the neural circuits that link the hypothalamus and brainstem are dependent on the activity of leptin-sensing AgRP neurons during a postnatal, critical period of hypothalamic development.
3. Perturbing of the neural activity in hypothalamic neurons can permanently alter the functional regulation of brainstem regions that coordinate gastrointestinal processes related to feeding.

The results reported in this paper should expand our appreciation of the developmental role that hormones such as leptin play in specifying the organization of neural circuits that control essential functions related to metabolic health and expression of disease risk. Although we have known for decades that neural activity impacts the development of the visual system and other sensory systems, the role of neuronal activity in mediating actions of hormones has been largely overlooked in studies of hypothalamic development, where the focus has been on receptor-mediated control of gene expression.

“The possibility that neural circuits that control something as fundamental as energy balance are sensitive to activity alone during key periods of development suggests that there may be a wide variety of factors impacting hypothalamic development through this mechanism,” Simerly said. “Exposure of the developing brain to molecules that alter neural activity may have lasting consequences when building key neural circuits, which may have lasting effects on how the brain functions in health and disease.”

This research opens the door to the possibility of harnessing this mechanism to facilitate normal development and improve outcomes for populations who are at risk due to genetic abnormalities or harmful environmental exposure.

The work described here would not have been possible without the talent and tenacity of staff scientist and first author Jessica Biddinger.  The contributions of collaborating author Julio Ayala, associate professor of molecular physiology and biophysics and director of the Vanderbilt Mouse Metabolic Phenotyping Center, were also integral to the work.

Reference: Biddinger JE, Elson AET, Fathi PA, et al. AgRP neurons mediate activity-dependent development of oxytocin connectivity and autonomic regulation. PNAS. 2024;121(49):e2403810121. doi: 10.1073/pnas.2403810121

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