2025 Theses Doctoral

The Role of Leptin in Metabolic Programming

Fohn, Alexis

A wide range of developmental exposures can influence the establishment of sympathetic nervous system (SNS) tone onto metabolically relevant organs, such as the pancreas, liver, kidney, and adipose tissues, but little is known about the underlying mechanism. Previous studies have shown that rearing mice at an ambient temperature of 30°C vs. 22°C from birth to 8 weeks of life programs lasting effects on SNS tone onto interscapular brown adipose tissue (BAT) and the capacity to respond to a chronic cold challenge.

We used this system to define a critical period of development and a molecular mediator of these effects. We compared the number of sympathetic neurons in the stellate ganglion labeled with a cholera toxin subunit B retrograde trace from BAT (SGBAT) across the first 8 weeks of life in C57BL6/J mice reared at 30°C vs. 22°C. There is a marked decrease in the number of SGBAT neurons after weaning in 30°C-reared mice until 8 weeks of age.

Analysis of the transcriptional profiles of BAT via bulk RNA-Seq in mice raised at 30°C vs. 22°C revealed that leptin is differentially expressed during the critical period. Complementary leptin gain- and loss-of-function studies support the idea that leptin expression in BAT, and not from the circulation, establishes BAT SNS tone during development. Mechanisms identified here will provide a framework for analogous studies of SNS tone in other organs that are also implicated in developmental programming of health and disease.