posted on 2022-01-26, 18:24authored byQianyi Yang, Jameson Hinkle, Jordan N. Reed, Redouane Aherrahrou, Zhiwen Xu, Thurl E. Harris, Erin J. Stephenson, Kiran Musunuru, Susanna R. Keller, Mete Civelek
Genome-wide association studies identified single nucleotide
polymorphisms on chromosome 7 upstream of KLF14 to be associated with
metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D).
The associations were more significant in women than in men. The risk
allele carriers expressed lower levels of the transcription factor KLF14
in adipose tissues than non-risk allele carriers. To investigate how
adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we
characterized high-fat diet fed male and female mice with
adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion
resulted in increased fat mass in female mice and decreased fat mass in
male mice. Female Klf14-deficient mice had overall smaller adipocytes in
subcutaneous fat depots but larger adipocytes in parametrial depots,
indicating a shift in lipid storage from subcutaneous to visceral fat
depots. They had reduced metabolic rates and increased respiratory
exchange ratios consistent with increased utilization of carbohydrates
as an energy source. Fasting and isoproterenol-induced adipocyte
lipolysis was defective in female Klf14-deficient mice and concomitantly
adipocyte triglycerides lipase mRNA levels were downregulated. Female
Klf14-deficient mice cleared blood triglyceride and NEFA less
efficiently than wild type. Finally, adipocyte-specific overexpression
of Klf14 resulted in lower total body fat in female but not male mice.
Taken together, consistent with human studies, adipocyte KLF14
deficiency in female but not in male mice causes increased adiposity and
redistribution of lipid storage from subcutaneous to visceral adipose
tissues. Increasing KLF14 abundance in adipocytes of females with
obesity and T2D may provide a novel treatment option to alleviate
metabolic abnormalities.
Funding
American Diabetes Association 1-19-IBS-105 U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases R01 DK118287