Skip to main content
ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #365254
Title: Sex modulates hepatic mitochondrial adaptations to high fat diet and physical activity

Author
item MCCOIN, COLIN - University Of Arkansas
item SCHULZE, ALEX VON - University Of Kansas Medical School
item ALLEN, JULIE - University Of Kansas Medical School
item FULLER, KELLY NZ - University Of Kansas Medical School
item XIA, QING - University Of Kansas Medical School
item KOESTLER, DEVIN C. - University Of Kansas Medical School
item HOUCHEN, CLAIRE J. - University Of Kansas Medical School
item MAURER, ADRIANNA - University Of Kansas Medical School
item DORN II, GERALD W. - Washington University School Of Medicine
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)
item MORRIS E., MATTHEW - University Of Kansas Medical School
item THYFAULT, JOHN P. - University Of Kansas Medical School

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/29/2019
Publication Date: 4/30/2019
Citation: McCoin, C.S., Schulze, A., Allen, J., Fuller, K., Xia, Q., Koestler, D., Houchen, C., Maurer, A., Dorn II, G., Shankar, K., Morris E., M., Thyfault, J. 2019. Sex modulates hepatic mitochondrial adaptations to high fat diet and physical activity. American Journal of Physiology - Endocrinology and Metabolism. https://doi.org/10.1152/ajpendo.00098.2019.
DOI: https://doi.org/10.1152/ajpendo.00098.2019

Interpretive Summary: Sex has a predominant effect on the risk of a number of metabolic diseases. However the impact of sex on differences in mitochondrial function remain unclear. Mice with free access to running wheels spontaneously increase their activity and have better functioning mitochondria, the primary energy powerhouses of a cell. To understand the role of specific proteins important in mitochondrial function on the ability to adapt during following exercise and high-fat diets, mice were provided either low or high fat diet with and without access to running wheels. These studies showed that female mice showed better mitochondrial function and male mice required exercise to elicit mitochondrial changes in response to high fat diets. Overall these studies point to an important role of intrinsic sex differences in mitochondrial adaptations to diet and exercise.

Technical Abstract: The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific PGC-1a, a transcriptional co-activator of biogenesis, and BNIP3, a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2 production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild type (WT), liver-specific PGC-1a heterozygote (LPGC-1a) and BNIP3 null mice were thermoneutral housed (29-31 degree C) and divided into three groups: sedentary - low fat diet (LFD), 16 weeks of (HFD), or 16 weeks of HFD with VWR for the final 8 weeks (HFD+VWR) (n=5-7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group, however HFD+VWR significantly increased maximal respiratory capacity only in WT and PGC-1a females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling efficiency and reduced H2O2 production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1a and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD+VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1a or BNIP3.