Abstract Body: Obesity is a risk factor of cardiovascular diseases including atherosclerosis. Sustained weight loss has beneficial effects on these diseases. However, 80 % of people regain weight and observational studies have shown that this has detrimental effects on cardiovascular diseases. The pathways that lead to improvement upon weight loss and decline after weight regain, however, are not fully understood. Previous studies have shown that weight loss in mice leads to epigenetic changes in myeloid cells and their precursors, cell types crucial in atherosclerosis. Here, we hypothesize that epigenetic changes in myeloid (precursor) cells due to weight cycling adversely affect atherosclerosis.
We show in mice that weight loss induced by short term (2 weeks) caloric restriction (stCR) results in lower mRNA expression levels of inflammatory markers Tnf and Nos2 in bone marrow (BM) cells compared to those of obese mice (Ob), while weight regain (WR) increases those levels: (Tnf Ob: 0.034 ± 0.007, stCR: 0.0188 ± 0.0023, WR: 0.045 ± 0.002 and Nos2 Ob: 0.134 ± 0.015, CR: 0.072 ± 0.009, WR: 0.1306 ± 0.01855, n=7-10). We observed the same pattern in LPS stimulated BM cells (Tnf Ob: 0.411 ± 0.062, stCR: 0.203 ± 0.025, WR: 0.564 ± 0.047 and Nos2 Ob: 0.161 ± 0.020, stCR: 0.098 ± 0.009, WR: 0.228 ± 0.031, n=7-10). We then examined if these ex vivo responses can be extended in vivo. BM from Ob, stCR or WR mice was transplanted into lean, Ldlr^-/- mice placed on high-cholesterol diet for 16 weeks. We observed that the weight cycling-induced changes to myeloid precursor cells contributed to atherosclerotic plaque development. This is indicated by a worsening in plaque characteristics, such as collagen content, a marker of stability in human plaques (Ob recipient: 0.355 % ± 0.054, stCR recipient: 0.487 % ± 0.088, WR recipient: 0.233 % ± 0.057, n=8-9) and necrotic core, a marker of plaque vulnerability in human plaques (Ob recipient: 4.648 % ± 1.026, stCR recipient: 1.937 % ± 0.426, WR recipient: 5.863 % ± 1.456, n=5-6) in the WR BM recipient Ldlr^-/- mice compared to stCR BM recipients. All comparisons between stCR and WR are significant at p< 0.05.
In conclusion, these data support the hypothesis that weight cycling induces epigenetic changes in myeloid cells which have effects on atherosclerosis. Ongoing studies are defining these changes and such data will advance the mechanistic knowledge by which weight cycling promotes atherogenesis and potentially other inflammatory conditions.