Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J Mice

Authors: Larson, Kate; Bundy, Amy; LANCE, ELIZABETH - University Of North Dakota; Casperson, Shanon; DARLAND, DIANE - University Of North Dakota; Roemmich, James

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/29/2021
Publication Date: 7/30/2021
Citation: Larson, K.J., Bundy, A.N., Lance, E.B., Casperson, S.L., Darland, D.C., Roemmich, J.N. 2021. Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J Mice. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2021.108853.
DOI: https://doi.org/10.1016/j.jnutbio.2021.108853

Interpretive Summary: Using a mouse model, we investigated whether offspring exercise reduces obesity and type 2 diabetes (T2D) risk caused by a maternal high fat (HF) diet. For this study, two-month old female C57Bl/6J mice (F0 generation) were fed a normal fat (NF) 16% diet or a 45% HF diet for 3 months prior to breeding, and subsequent gestation and lactation. Male offspring (F1 generation) were fed the same NF and HF diets and further divided into either sedentary (S) or voluntary wheel running (Ex) groups for an additional 3 months. Since we previously showed that maternal and paternal diets regulate offspring obesity and T2D risk by altering methylation status of G9a protein (Histone3 Lysine9 dimethyl transferase) and metabolically active beige adipocyte (BA)(positive for cell surface marker called fibroblast growth factor 21 or FGF21) we measured expression of G9a, G9a associated factors (E4BP4), and G9a inhibitor (KDM4C). Results showed that postnatal HF diet decreased BA numbers and FGF21 expression compared to NF diet. G9a and E4BP4 protein expression patterns were opposite when sedentary conditions were compared to exercised conditions. Interestingly, under exercised condition, postnatal HF diet induced KDM4C protein expression while no changes in KDM4C protein expression were induced under sedentary conditions. These data indicate that offspring HF diet induced reduction in BA and FGF21 is minimized by reducing G9a by offspring exercise via increasing KDM4C expression. Future studies need to determine whether KDM4C induces methylation status of G9a to alter thermogenic function of BA needs to be investigated.

Technical Abstract: Maternal low-protein and postnatal high-fat (HF) diets program offspring obesity and type 2 diabetes mellitus (T2DM) risk by epigenetically reducing beige adipocytes (BA) via increased G9a protein expression (Histone3 Lysine9 dimethyl transferase), an inhibitor of the BA marker fibroblast growth factor 21 (FGF21). Conversely, offspring exercise reduces fat mass and white adipocytes, but the mechanisms are not yet understood. This work investigated whether exercise reduces offspring obesity and T2DM risk caused by a maternal HF diet via regulation of G9a and FGF21 expression that would convert white to BA. Two-month old female C57Bl/6J mice (F0) were fed a normal fat (NF) 16% diet or a 45% HF diet for 3 months prior to breeding, and subsequent gestation and lactation. Male offspring (F1) were fed the same NF and HF diets and further divided into either sedentary (S) or voluntary wheel running (Ex) groups for an additional 3 months yielding eight groups: NF (maternal treatment condition)-NF-S (post weaning treatment conditions), NF-HF-S, NF-NF-Ex, NF-HF-Ex, HF-NF-S, HF-HF-S, HF-NF-Ex, and HF-HF-Ex. Subcutaneous adipose tissue (ScAT) was collected for protein and mRNA analysis of FGF21, peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha, inducer of FGF21), G9a, E4BP4 (G9a coactivator), and protein expression of H3K9 demethylases (KDM4C). Postnatal HF diet decreased FGF21 positive BA numbers regardless of maternal diets and postnatal diet and exercise. Under sedentary conditions, postnatal HF diet increased protein expression of FGF21 transcription inhibitors G9a and E4BP4 compared to NF diet resulting in decreased FGF21 expression. In contrast, postnatal HF diet and exercise decreased G9a and E4BP4 protein expression while decreasing FGF21 expression compared to NF diet. Under exercised condition, postnatal HF diet induced KDM4C protein expression while no changes in KDM4C protein expression were induced by postnatal HF diet under sedentary conditions. These findings suggest that the postnatal diet exerts a greater impact on offspring adiposity and BA numbers than maternal diets. These data also suggest that offspring exercise induces KDM4C to counter the increase in G9a that was triggered by maternal and postnatal HF diets. Future studies need to determine whether KDM4C induces methylation status of G9a to alter thermogenic function of BA needs to be investigated.