Document Type

Honors Thesis

Semester of Graduation

Spring 2026

Abstract

Historically, low insulin levels were the signaling event considered responsible for metabolic adaptations to starvation, such as increased sympathetic outflow and increased serum levels of ketones, glucagon, and free fatty acids. Leptin, a hormone produced by adipose tissue, is known to decrease in response to caloric restriction. Recent work in the field suggested that leptin infusion in the final hours of a 48-hour fast reversed all metabolic adaptations to starvation, thus raising questions about an underappreciated role of leptin in the starvation response. This study tested whether physiological leptin replacement, maintaining fed plasma leptin concentrations, during a 72-hour fast in rats was sufficient to reverse the physiological adaptations to starvation. Sprague-Dawley rats were subjected to a 72-h fast with/without physiological leptin replacement (n=6/n=6), or ad libitum feeding (control, n=7). Leptin replacement was achieved via iPrecio programmable mini-pumps. Metabolite and hormone levels were measured at baseline and every 24 hours during the fasting period. Data were tested for significant differences between 72-hour fast and 72-hour fast+leptin or control groups at each time point using 2-way ANOVA. Expected trends were observed in blood glucose and body weight in 72-h fasted group relative to fed controls (p < 0.001). Additionally, while leptin levels fell in 72-h fasted group relative to controls, there was no significant difference in leptin levels between ad libitum controls and the 72-h fast+leptin group (all p > 0.17), confirming the efficacy of our unique leptin replacement technique. Interestingly, peak plasma corticosterone levels were significantly reduced in 72-h fast+leptin group relative to 72-h fast group (p = 0.05). Despite recent reports citing leptin as a key mediator of metabolic adaptations to starvation, our data generally show that key changes in metabolites associated with starvation are unchanged by physiological leptin replacement during fasting. Leptin treatment had no effect on sympathetic tone, weight loss, or glucose homeostasis during the fast, although peak corticosterone levels were blunted in the leptin-treated group. Future directions include expanded analysis of changes in hormones and metabolites during the fast to include glucagon, ketones, and free fatty acids, with similar analysis in females.

Awardee Name

Sydney Junot

Academic Major

Biological Sciences

Project Mentor

David McDougal

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