Abstract

Hepatocytes integrate signals from macronutrients and the intrinsic circadian clock to optimize fuel utilization. An intact core circadian clock is required to maintain normal metabolism, yet the integration of the clock with nutritive signals remains unclear. My dissertation focuses on defining the metabolic functions of the core circadian gene Period 1 (Per1) under diverse metabolic conditions. We identified Per1 as the only core circadian gene significantly upregulated during acute fasting. Using a mouse model with loxP sites flanking exon 4 and exon 10 of Per1, we generated hepatocyte-specific Per1 knockout mice via hepatocyte-targeted Cre recombinase. In the first section of this dissertation, we demonstrate that hepatocyte Per1 is required for proper fasting adaptation. Depletion of hepatocyte Per1 impairs peripheral lipolysis, autophagy, and the metabolic switch from glucose to fatty acid oxidation. Mechanistically, we identified a Per1–Fgf21–Pdk4 axis that mediates these key hepatic fasting responses. We next investigated the role of Per1 in diet-induced obesity using the same model subjected to a 12-week Western diet feeding. Hepatocyte-specific Per1 deficiency increases susceptibility to obesity, characterized by impaired glucose homeostasis and enhanced activation of lipogenic pathways, resulting in increased hepatic lipid accumulation. Conversely, overexpression of Per1, as well as two structurally deficient mutants, is sufficient to improve glucose metabolism and suppress hepatic steatosis. Mechanistically, we uncovered a PER1–PP2A–ChREBP signaling pathway through which Per1 inhibits lipogenesis. Notably, one truncated mutant consisting of only 144 amino acids retains metabolic efficacy, highlighting its therapeutic potential for obesity and associated fatty liver disease. Finally, we examined whether hepatocyte Per1 mediates the metabolic benefits of time-restricted feeding under high-fat diet condition. Male and female mice with or without hepatocyte Per1 were subjected to either ad libitum feeding or time-restricted feeding during the dark cycle. Female mice were relatively protected from diet-induced obesity and showed minimal benefit from time-restricted feeding. In contrast, male mice exhibited reduced weight gain and improved glucose and energy homeostasis under time-restricted feeding, independent of hepatocyte Per1. In summary, this dissertation systematically defines the role of hepatocyte Per1 in fasting adaptation, diet-induced obesity, and time-restricted feeding. These findings reveal a previously unrecognized function of Per1 in linking the intrinsic circadian clock to nutritional signaling, providing new insight into metabolic regulation and potential therapeutic strategies.

Committee Chair

Brian DeBosch

Committee Members

Brian Finck; Erik Herzog; Irfan Lodhi; Jeffrey Haspel

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

7-24-2026

Language

English (en)

Download

Available for download on Saturday, January 23, 2027

Share

COinS