Excess intramuscular lipids are thought to play a causal role in insulin resistance. As such, examination of pathways involved in lipid uptake, storage and catabolism has provided great insight into mechanisms of lipid- induced insulin resistance. It is clear that lipid storage outpaces lipid catabolism in models of insulin resistanc, thus strategies designed to reduce cellular lipid accumulation offer therapeutic potential. Much research has investigated aspects of these pathways; however, the importance of peroxisomes in insulin resistance remains largely unknown. This may be a critical oversight as peroxisomes are almost exclusively involved in lipid metabolism. With this in mind, the presence of ?, , and ?-oxidative pathways provides them with the capacity to metabolize a broad spectrum of lipids. With this extensive network of catabolic pathways, the study of peroxisomal function in lipid-induced insulin resistance seems likely to yield important insight relevant to the pathogenesis of this metabolic disease. The focus of my laboratory is to bridge this gap in knowledge. We have found peroxisomes are elevated in insulin resistant skeletal muscle. Alternatively, we have also consistently seen heightened peroxisomes in muscle from models protected from developing insulin resistance (increased aerobic capacity, caloric restriction, methionine restriction, and muscle-specific CPT1b deficiency). In combination, these results lead us to predict that the increase in peroxisomes in response to lipid-induced insulin resistance is a protective mechanism designed to alleviate a lipotoxic environment; however, this remains speculative. We will test this hypothesis in Specific Aims 1 & 2 by abrogating peroxisomal function and determining if this 1) results in a predisposition toward insulin resistance, and 2) limits the therapeutic effects of insulin sensitizing interventions (caloric restriction, exercise and muscle-specific CPT1b deficiency). Our studies show peroxisomal responses in muscle often differ than those in liver. This poses an interesting conundrum as most information regarding peroxisomal regulation has been established in the liver. If we are to achieve our long-term goal of using results from these studies to develop an approach targeting peroxisomes that offers therapeutic potential, it is critical to gain a mechanistic understanding of pathways that dictate peroxisomal adaptations in skeletal muscle. In this regard, our evidence leads us to hypothesize that peroxisomes in muscle are responsive to energy status and PGC1? is a primary regulator of these responses. This will be tested in Specific Aim 3 where peroxisomal adaptations will be monitored in muscle-specific, PGC1?-deficient models (myotubes and mouse models) in response to stimuli that induce peroxisomes (AICAR, resveratrol, high fat diet, exercise and caloric restriction). Collectively, results from Aims 1 & 2 are expected to yield insight that will define the role of skeletal muscle peroxisomes in glucose homeostasis, while findings from Aim 3 are designed to provide mechanistic insight as to how future investigations can be designed to develop strategies that regulate peroxisomal function in skeletal muscle to treat insulin resistance.

Public Health Relevance

Excess accumulation of lipid within skeletal muscle is thought to play a causal role in the development of insulin resistance, thus strategies aimed at reducing this lipid burden offer therapeutic potential. Peroxisomes are organelles that have the ability to break down lipids, yet their relative importance in insulin resistance remains unknown. Our studies are designed to define the role of peroxisomes in insulin resistance and provide insight into whether strategies designed to manipulate peroxisomal function in skeletal muscle may provide a viable treatment option for this metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103860-04
Application #
9392162
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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