Voluntary wheel running improves adipose tissue immunometabolism in ovariectomized low-fit rats

Abstract

Loss of ovarian hormones is associated with increased adiposity, white adipose tissue (WAT) inflammation, and insulin resistance (IR). Previous work demonstrated ovariectomized (OVX) rats bred for high aerobic fitness (HCR) are protected against weight gain and IR compared to rats bred for low aerobic fitness (LCR) yet wheel running prevents OVX-induced IR in LCR rats. The purpose of this study was to determine whether adipose tissue immunometabolic characteristics from female HCR and LCR rats differs before or after OVX, and whether wheel running mitigates OVX-induced adipose tissue immunometabolic changes in LCR rats. Female OVX HCR and LCR rats were all fed a high fat diet (HFD) (n = 7-8/group) and randomized to either a running wheel or remain sedentary for 11 weeks. Ovary-intact rats (n = 7-12/group) were fed a standard chow diet with no wheel. Ovary-intact LCR rats had a greater visceral WAT inflammatory profile compared to HCR. Following OVX, sedentary LCR rats had greater serum leptin (p<0.001) and WAT inflammation (p<0.05) than sedentary HCR. Wheel running normalized the elevated serum leptin and reduced both visceral (p<0.05) and subcutaneous (p<0.03) WAT inflammatory markers in the LCR rats. Paradoxically, wheel running increased some markers of WAT inflammation in OVX HCR rats (p<0.05), which correlated with observed weight gain. Taken together, HCR rats appear to have a healthier WAT immune and metabolic profile compared to LCR, even following OVX. Wheel running improves WAT health in previously sedentary LCR rats. On the other hand, increased WAT inflammation is associated with adiposity gain despite a high volume of wheel running in HCR rats.

Keywords: inflammation; insulin resistance; intrinsic fitness; menopause; white and brown adipose tissue.

Figure 1.

Effects of OVX and wheel running on body composition in HCR and LCR rats. The data presented are summarized from previous findings.11, 23 (A) Body weight gain via (B) body fat % was examined in the (C) subcutaneous (SQAT), (D) total visceral depots (VAT) and (E) brown (BAT) depots. (F) relative BAT/VAT ratio. Calculations of (G) HOMA-IR and (H) Adipo-IR were completed to indirectly measure IR. *Indicates significant differences between ovary-intact (SHM) rats. Values are mean ± SEM (n = 5–10 per group); where p < 0.05 is statistically significant. L = line main effect, HCR vs. LCR; T = treatment main effect, SED vs. VWR; LxT = line by treatment interaction. NC = standard chow diet; HFD = high fat diet; SED = sedentary; VWR = voluntary wheel running.

Figure 2.

Effects of voluntary wheel running (VWR) on perigonadal WAT inflammation in OVX HCR and LCR rats. (A) % CD3 stromal vascular cells (SVCs), (B) % CD4 SVCs and (C) CD11c+ SVCs. Gene expression of inflammatory makers examined were (D) CD3, (E) CD4, and (F) CD11c (G) CD8, (H) TNFα, (I) IL-6, (J) F4/80, and (K) MCP1. *Indicates significant differences between ovary-intact (SHM) animals. Values are mean ± SEM (n=5–10 per group); where p < 0.05 is statistically significant. L = line main effect, HCR vs. LCR; T = treatment main effect, SED vs. VWR; LxT = line by treatment interaction. HFD = high fat diet; NC = standard normal chow; SED = sedentary.

Figure 3.

Effects of voluntary wheel running (VWR) on subcutaneous WAT inflammation in OVX HCR and LCR rats. Pro-inflammatory and macrophage marker mRNA expression. (A) CD3, (B) CD4, (C) CD11c, (D) CD8, (E) TNFα, (F) IL-6, (G) F4/80, and (H) MCP1. *Indicates significant differences between these groups. Values are mean ± SEM (n = 5–10 per group); where p < 0.05 is statistically significant. L = line main effect, HCR vs. LCR; T = treatment main effect, SED vs. VWR; LxT = line by treatment interaction. HFD = high fat diet; NC = standard normal chow; SED = sedentary; SHM = ovary-intact.

Figure 4.

Effects of voluntary wheel running (VWR) on interscapular BAT inflammation in OVX HCR and LCR rats. Pro-inflammatory and macrophage marker mRNA expression include (A) CD3, (B) CD4, (C) CD11c, (D) CD8, (E) TNFα, (F) IL-6, (G) F4/80, and (H) MCP1. *Indicates significant differences between ovary-intact (SHM) rats. Values are mean ± SEM (n=5–10 per group); where p < 0.05 is statistically significant. L = line main effect, HCR vs. LCR; T = treatment main effect, SED vs. VWR; LxT = line by treatment interaction. HFD = high fat diet; NC = standard normal chow; SED = sedentary.

Figure 5.

Wheel running reduces circulating and tissue expression levels of leptin in LCR rats. Circulating (A) adiponectin and (B) leptin and the (C) adiponectin to leptin ratio. mRNA expression for adiponectin (D) in perigonadal (VAT), (E) subcutaneous (SQAT) WAT, and (F) BAT depots; and leptin (G) in VAT, (H) SQAT, and (I) BAT depots. *Indicates significant differences between these groups. Values are mean ± SEM (n=5–10 per group); where p<0.05 is statistically significant. L = line main effect, HCR vs. LCR; T = treatment main effect, SED vs. VWR; LxT = line by treatment interaction. BAT = brown adipose tissue; HFD = high fat diet; NC = standard normal chow; SED = sedentary; SHM = ovary-intact; VWR = voluntary wheel running.

Figure 6.

Mitochondrial expression analyses across adipose tissue depots in HCR vs. LCR rats. Mitochondrial oxidative phosphorylation complexes I, II, III, IV, and V for (A-B) retroperitoneal WAT (VAT) and (D-E) BAT. Representative western blot images for (C) VAT and (F) BAT. *Indicates significant differences between ovary-intact (SHM) rats. Values are mean ± SEM; where p < 0.05 is statistically significant. L = line main effect, HCR vs. LCR; T = treatment main effect, SED vs. VWR; LxT = line by treatment interaction. BAT = brown AT; HFD = high fat diet; NC = standard normal chow; SED = sedentary; VWR = voluntary wheel running.