Obesity and particularly the metabolic syndrome are associated with both, type 2 diabetes based on insulin resistance and cardiovascular disease. Obesity induces adipose tissue inflammation, which plays a key role in the development of obesity-driven metabolic complications leading the way to type 2 diabetes and cardiovascular diseases [2, 5]. Our data show and confirm that both LDLR-/- and ApoE-/- mice develop diet-induced obesity on high-fat diets, while LDLR-/- mice are more prone to adipose tissue inflammation and insulin resistance in addition to atherosclerosis. Hence, this genetic background turned out to be more suitable for investigation of cardio-metabolic disease. Moreover, we show here that using sucrose rather than more complex carbohydrates in a high-fat diet significantly accelerated the development of obesity-induced adipose tissue inflammation, insulin resistance, impaired glucose tolerance and atherosclerosis in LDLR-/- mice leading to suitable readouts already after 12 to 16 weeks of dietary treatment.
After dietary treatment of LDLR-/- mice with HFSC or HFC for 16 weeks mice on HFSC revealed significantly more pronounced adipose tissue inflammation as shown by elevated adipose tissue expression of the inflammatory genes for F4/80, osteopontin and TNF-α Increased gene expression of F4/80, a typical macrophage marker, indicates macrophage accumulation, while increased osteopontin and TNF-αm RNA levels provide additional evidence for local inflammation. Strikingly, after four more weeks, adipose tissue inflammation in LDLR-/- mice fed HFSC or HFC reached similar levels of inflammatory gene expression suggesting that the high sucrose uptake speeds up rather than augments the detrimental effects of high-fat and cholesterol-rich diets. In addition to adipose tissue inflammation, LDLR-/- mice fed HFSC further demonstrated increased hepatic inflammation compared to HFC-fed LDLR-/- mice after 16 weeks of feeding while these differences evened out after 20 weeks. These results may indicate an important role of dietary macronutrient composition e.g. on inflammatory alterations which grossly exceeds its effect on body weight [37–39].
At earlier time points, we observed marked differences in adipose tissue inflammation, insulin levels, HOMA-IR, and glucose tolerance between the LDLR-/- animals on HFSC and those on HFC while the insulin tolerance test did not show significant differences suggesting that whole body insulin resistance was not affected by HFSC. Strikingly, after 20 weeks on diet, the stabilization of adipose tissue inflammation was mirrored by comparable levels of fasting insulin and HOMA-IR, which on the one hand might support the notion that adipose tissue inflammation contributes to insulin resistance [6, 40]. On the other hand, this observation could be due to the fact that after a certain time span of feeding maximal biological effects might be reached in HFSC-fed LDLR-/- mice and thus reach a plateau while HFC-fed LDLR-/- mice then “catch up” with the HFSC-fed group. In general this might be an issue of many experimental diets which are often very extreme in their composition to reach maximum biological effects very fast. Moreover, although body weight after dietary treatment of LDLR-/- mice with HFSC or HFC for 12 weeks did not differ, total body weight exposure (area under the body weight curve) was moderately higher in HFSC- compared to HFC-fed group (LDLR-/- mice on HFSC: 807 ± 23 and HFC: 737 ± 14), which could also contribute to difference in metabolic parameters at this time point.
Notably, mice on both diets used in this study appeared healthy at any time point, which is an advantage over the widely used Western Diets which reportedly leads to changes in fur and skin integrity even leading to ulceration or sudden weight loss .
After 16 weeks of diet LDLR-/- mice on HFSC but not on HFC developed atherosclerotic lesion areas comparable to the commonly used ApoE-/- model. The significant early increase of total plasma cholesterol as well as an increase of VLDL and LDL cholesterol levels in HFSC-fed LDLR-/- mice may certainly contribute to plaque formation and represent major risk factors for atherosclerosis . On the other hand, the marked adipose tissue inflammation and insulin resistance in HFSC-fed animals might further suggest an association between obesity-induced inflammation and atherosclerotic plaque formation which was described in murine models  and is evident in clinical trials [44, 45].
In addition to increased osteopontin mRNA levels in adipose tissue and liver, plasma osteopontin was in trend upregulated by the sucrose-enriched high-fat diet (HFSC; P = 0.077), but not the common high-fat diet (HFC) confirming earlier results that high-fat diet locally upregulates osteopontin in tissue but not in plasma . HFSC-induced elevated plasma osteopontin could be directly related to its upregulation by glucose, which was shown in vascular smooth muscle cells and arteries of diabetic patients [47, 48]. Thus, osteopontin seems to primarily act locally and is closely related to atherosclerotic disease and cardiovascular events in patients .
In humans it is well known that diets with a high dietary glycemic load lead to inflammation, insulin resistance and impaired beta-cell function [20, 22] and promote weight gain . Of course one has to bear in mind that mice used in this study were of C57BL/6 background which is known to have smaller islet mass and more prominent islet inflammation than other mouse strains,  but C57BL/6 are a widely accepted mouse model for obesity-associated complications.
Here we show that in LDLR-/- mice addition of sucrose to a high-fat diet induces earlier and more pronounced adipose tissue inflammation, insulin resistance, glucose intolerance and atherosclerosis. As sucrose consists of both fructose and glucose our findings of worsened cardio-metabolic situation in LDLR-/- mice fed HFSC may be due to the high glycemic load on the one hand and fructose-induced adverse effects on the other hand. E.g. sucrose could partly contribute to accelerated inflammation through fructose, which has been shown to activate inflammatory pathways such as NF-κB signaling and to induce oxidative stress in animal models which might further contribute to inflammatory alterations [52–54]. Moreover, fructose in high amounts has been shown to decrease insulin sensitivity more than glucose and to induce ectopic and visceral fat deposition, de novo lipogenesis, higher blood pressure and blood uric acid concentrations [23, 55]. The fact that fructose absorption is enhanced in presence of glucose , may explain why fructose-enriched diets alone could not induce insulin resistance in LDLR-/- mice .