Degree

Master of Science (MS)

Department

Kinesiology

Document Type

Thesis

Abstract

Skeletal muscle plays a central role in whole-body lipid metabolism through mitochondrial and peroxisomal fatty acid oxidation (FAO). When skeletal muscle lipid metabolism is impaired, whole-body adaptations occur to maintain metabolic homeostasis. We hypothesized that limiting skeletal muscle lipid metabolism through mitochondria and/or peroxisomes would trigger adaptive responses to reduce dietary lipid intake and/or absorption with the most robust changes coinciding with deficit severity. Mice were generated with skeletal muscle-specific deletion of 1) carnitine palmitoyltransferase 1b (Cpt1bM-/-) to limit mitochondrial FAO, 2) peroxin 5 (Pex5M-/-) to impair peroxisomal FAO, and 3) both Cpt1b and Pex5 (DKO). Results were compared to floxed littermate controls (Cpt1bfl/fl, Pex5fl/fl, and DFL). Skeletal muscle FAO capacity was reduced 20-30% in Cpt1bM-/- and Pex5M-/- mice, while DKO mice had a 60-70% decrease. Despite these deficits, only Cpt1bM-/- mice had impaired whole-body lipid clearance after Intralipid 20 gavage (15µl/g body weight). Further tests revealed distinct adaptive responses: Cpt1bM-/- mice reduce dietary lipid intake, while DKO mice limit dietary lipid absorption (no changes in Pex5M-/- mice). Investigation of circulating factors that may contribute to these unique responses showed that Cpt1bM-/- mice produced fibroblast growth factor 21 (Fgf21), growth differentiation factor 15 (Gdf15), and angiopoietin-like 4 (Angptl4), which enter circulation and can impact food/lipid preference. In contrast, serum proteomics revealed that DKO mice released mitochondrial proteins into the circulation that are predicted to alter dietary lipid absorption. Skeletal muscle can communicate the severity of deficit in FAO capacity to finetune dietary lipid intake and absorption, potentially through release of distinct musclederived proteins into the circulation.

Date

2-6-2026

DOI

https://proquest.com/docview/3347960524

First Committee Chair

Peter Smoak

First Committee Member

Charles Duncan

Second Committee Member

Ismatara Reena

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