Considerable evidence supports the idea that oversupply of dietary fat exceeds the storage capacity of adipose tissue and leads to ectopic lipid accumulation resulting in """"""""metabolic stress"""""""" in skeletal muscle, liver, pancreas and possibly other tissues, leading to insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) leads to the cytosolic accumulation of lipid intermediates that are directly linked to defects in insulin signalin. Others report lipid oversupply via a high fat diet can actually increase FAO to the extent that carnitine and TCA cycle intermediates are limiting, leading to mitochondrial abnormalities and skeletal muscle insulin resistance. Thus, evidence exists that both lipotoxicity and mitochondrial dysfunction contribute to skeletal muscle insulin resistance. Determining if and how these are intertwined is one of the hottest topics in type 2 diabetes research, with the fundamentally important question being: Does inhibition of FAO in skeletal muscle contribute to insulin resistance? To address this question we created mice lacking Carnitine Palmitoyltransferase-1b (CPT-1b) in muscle (CPT-1bm-/-). As predicted, CPT-1bm-/- mice have decreased mitochondrial FAO, increased IMCL, increased circulating free fatty acids (FFA) and triglycerides (TG), and decreased physical activity and exercise endurance. However, CPT-1bm-/- mice are not insulin resistant and have decreased circulating insulin and glucose, improved insulin and glucose tolerance, increased pyruvate oxidation, and increased whole body carbohydrate oxidation. At first glance, the lack of insulin resistance in spite of having hallmark predictors of the disease is at odds with prevailing lipotoxic theories. Indeed, it indicates that CPT-1bm-/- mice undergo unique adaptations to maintain insulin sensitivity in the face of decreased skeletal muscle FAO. Preliminary studies reveal potentially significant alterations promoting lipid uptake and storage, mitochondrial biogenesis, enhanced peroxisomal FAO, and stimulation of factors linked to the mTor signaling cascade.
Specific Aim 1 : Employ dietary and genetic manipulations in CPT-1bm-/- mice to gain a better understanding of acute and chronic consequences of mitochondrial FAO inhibition.
Specific Aim 2 : To evaluate the effects of decreased CPT-1b on glucose and fatty acid uptake and storage, mitochondrial number and function, and peroxisomal FAO.
Specific Aim 3 : To investigate how energy deficit signals are transduced through nutrient sensitive pathways to influence insulin sensitivity. These innovative studies will test the lipotoxic hypothesis and the mitochondrial overload hypothesis in a more definitive manner, providing critical mechanistic information on the role of CPT-1b and FAO in mitochondrial function and insulin resistance.

Public Health Relevance

The prevalence of diabetes mellitus in the United States is reaching epidemic proportions and accounts for a huge national burden of morbidity, mortality, and health care expenditures. These studies ask the fundamentally important question: Does inhibition of fatty acid oxidation in skeletal muscle contribute to insulin resistance? These resuls could possibly facilitate the development of highly specific, novel interventions without undesirable side effects

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK098687-01A1
Application #
8632087
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2013-09-17
Project End
2018-06-30
Budget Start
2013-09-17
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$321,900
Indirect Cost
$104,400
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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