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Surplus fat rapidly increases fat oxidation and insulin resistance in lipodystrophic mice.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Girousse, Amandine 
Virtue, Samuel 
Hart, Dan 
Vidal-Puig, Antonio  ORCID logo  https://orcid.org/0000-0003-4220-9577
Murgatroyd, Peter R 

Abstract

OBJECTIVE: Surplus dietary fat cannot be converted into other macronutrient forms or excreted, so has to be stored or oxidized. Healthy mammals store excess energy in the form of triacylgycerol (TAG) in lipid droplets within adipocytes rather than oxidizing it, and thus ultimately gain weight. The 'overflow hypothesis' posits that the capacity to increase the size and number of adipocytes is finite and that when this limit is exceeded, fat accumulates in ectopic sites and leads to metabolic disease. METHODS: Here we studied the energetic and biochemical consequences of short-term (2-day) excess fat ingestion in a lipodystrophic (A-ZIP/F-1) mouse model in which adipose capacity is severely restricted. RESULTS: In wildtype littermates, this acute exposure to high fat diets resulted in excess energy intake and weight gain without any significant changes in macronutrient oxidation rates, glucose, TAG, or insulin levels. In contrast, hyperphagic lipodystrophic mice failed to gain weight; rather, they significantly increased hepatic steatosis and fat oxidation. This response was associated with a significant increase in hyperglycemia, hyperinsulinemia, glucosuria, hypertriglyceridemia, and worsening insulin tolerance. CONCLUSIONS: These data suggest that when adipose storage reserves are saturated, excess fat intake necessarily increases fat oxidation and induces oxidative substrate competition which exacerbates insulin resistance resolving any residual energy surplus through excretion of glucose.

Description

Keywords

Energy partitioning, Fatty acid oxidation, Insulin resistance, Lipodystrophy, Substrate competition, Adipocytes, Adipose Tissue, Adiposity, Animals, Diet, High-Fat, Dietary Fats, Energy Intake, Energy Metabolism, Fatty Liver, Glucose, Hyperinsulinism, Insulin Resistance, Lipids, Lipodystrophy, Liver, Mice, Obesity, Oxidation-Reduction, Weight Gain

Journal Title

Mol Metab

Conference Name

Journal ISSN

2212-8778
2212-8778

Volume Title

13

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (107064/Z/15/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (G0802051)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_UU_12012/2)
Medical Research Council (G0600717)
Medical Research Council (MC_G0802535)
Medical Research Council (G0400192)
MRC (MC_UU_00014/2)
MRC (MC_UU_00014/5)
Medical Research Council (MC_PC_12012)