Rosiglitazone improves survival and hastens recovery from pancreatic inflammation in obese mice

Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice.     

Adipose tissue‐specific modulation of galectin expression in lean and obese mice: Evidence for regulatory function

Objective:

Galectins (Gal) exert many activities, including regulation of inflammation and adipogenesis. We evaluated modulation of Gal‐1, ‐3, ‐9 and ‐12 in visceral (VAT) and subcutaneous (SAT) adipose tissue in mice.

Design and Methods:

We used two mouse models of obesity, high‐fat diet induced obesity (DIO) and ob/ob mice. We also evaluated the response of Gal‐1 KO mice to DIO.

Results:

Both age and diet modulated expression of galectins, with DIO mice having higher serum Gal‐1 and Gal‐3 versus lean mice after 13‐17 weeks of high‐fat diet. In DIO mice there was a progressive increase in expression of Gal‐1 and Gal‐9 in SAT, whereas Gal‐3 increased in both VAT and SAT. Expression of Gal‐12 declined over time in VAT of DIO mice, similar to adiponectin. Obesity lead to increased production of Gal‐1 in adipocytes, whereas the increased Gal‐3 and Gal‐9 of obesity mostly derived from the stromovascular fraction. Expression of Gal‐12 was restricted to adipocytes. There was increased production of Gal‐3 and Gal‐9, but not Gal‐1, in CD11c^? and CD11c⁺ macrophages from VAT of DIO versus lean mice. Expression of Gal‐1, ‐3 and ‐12 in VAT and SAT of ob/ob mice followed a trend comparable to DIO mice. Rosiglitazone reduced serum Gal‐1, but not Gal‐3 and modulated expression of Gal‐3 in VAT and Gal‐9 and Gal‐12 in SAT of DIO mice. High‐fat feeding lead to increased adiposity in Gal‐1 KO versus WT mice, with loss of correlation between leptin and adiposity and no alterations in glucose and insulin levels.

Conclusions:

Obesity leads to differential modulation of Gal‐1, 3, 9 and 12 in VAT and SAT, with Gal‐1 acting as a modulator of adiposity.

     

A dairy‐based high calcium diet improves glucose homeostasis and reduces steatosis in the context of preexisting obesity

Objective:

High dietary calcium (Ca) in the context of a dairy food matrix has been shown to reduce obesity development and associated inflammation in diet‐induced obese (DIO) rodents. The influence of Ca and dairy on these phenotypes in the context of preexisting obesity is not known. Furthermore, interpretations have been confounded historically by differences in body weight gain among DIO animals fed dairy‐based protein or high Ca.

Design and Methods:

Adiposity along with associated metabolic and inflammatory outcomes were measured in DIO mice previously fattened for 12 week on a soy protein‐based obesogenic high fat diet (45% energy, 0.5% adequate Ca), then fed one of three high fat diets (n = 29‐30/group) for an additional 8 week: control (same as lead‐in diet), high‐Ca (1.5% Ca), or high‐Ca + nonfat dry milk (NFDM).

Results and Conclusion:

Mice fed high‐Ca + NFDM had modestly, but significantly, attenuated weight gain compared to mice fed high‐Ca or versus controls (P < 0.001), whereas mice fed high‐Ca alone had increased weight gain compared to controls (P < 0.001). Total measured adipose depot weights between groups were similar, as were white adipose tissue inflammation and macrophage infiltration markers (e.g. TNFα, IL‐6, CD68 mRNAs). Mice fed high‐Ca + NFDM had significantly improved glucose tolerance following a glucose tolerance test, and markedly lower liver triglycerides compared to high‐Ca and control groups. Improved metabolic phenotypes in prefattened DIO mice following provision of a diet enriched with dairy‐based protein and carbohydrates appeared to be driven by non‐Ca components of dairy and were observed despite minimal differences in body weight or adiposity.     

Interleukin‐15 Contributes to the Regulation of Murine Adipose Tissue and Human Adipocytes

An alarming global rise in the prevalence of obesity and its contribution to the development of chronic diseases is a serious health concern. Recently, obesity has been described as a chronic low‐grade inflammatory condition, influenced by both adipose tissue and immune cells suggesting proinflammatory cytokines may play a role in its etiology. Here we examined the effects of interleukin‐15 (IL‐15) on adipose tissue and its association with obesity. Over expression of IL‐15 (IL‐15tg) was associated with lean body condition whereas lack of IL‐15 (IL‐15^?/?) results in significant increase in weight gain without altering appetite. Interestingly, there were no differences in proinflammatory cytokines such as IL‐6 and tumor necrosis factor‐α (TNF‐α) in serum between the three strains of mice. In addition, there were significant numbers of natural killer (NK) cells in fat tissues from IL‐15tg and B6 compared to IL‐15^?/? mice. IL‐15 treatment results in significant weight loss in IL‐15^?/? knockout and diet‐induced obese mice independent of food intake. Fat pad cross‐sections show decreased pad size with over expression of IL‐15 is due to adipocyte shrinkage. IL‐15 induces weight loss without altering food consumption by affecting lipid deposition in adipocytes. Treatment of differentiated human adipocytes with recombinant human IL‐15 protein resulted in decreased lipid deposition. In addition, obese patients had significantly lower serum IL‐15 levels when compared to normal weight individuals. These results clearly suggest that IL‐15 may be involved in adipose tissue regulation and linked to obesity.     

Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity

Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6-8 weeks of age were fed a high fat (n = 18) or regular (n = 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P = 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH; P = 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH; P < 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.     

Characterization of β‐Cell Mass and Insulin Resistance in Diet‐induced Obese and Diet‐resistant Rats

The selectively bred diet‐induced obese (DIO) and diet‐resistant (DR) rats represent a polygenetic animal model mimicking most clinical variables characterizing the human metabolic syndrome. When fed a high‐energy (HE) diet DIO rats develop visceral obesity, dyslipidemia, hyperinsulinemia, and insulin resistance but never frank diabetes. To improve our understanding of the underlying cause for the deteriorating glucose and insulin parameters, we have investigated possible adaptive responses in DIO and DR rats at the level of the insulin‐producing β‐cells. At the time of weaning, DR rats were found to have a higher body weight and β‐cell mass compared to DIO rats, and elevated insulin and glucose responses to an oral glucose load. However, at 2.5 months of age, and for the remaining study period, the effect of genotype became evident: the chow‐fed DIO rats steadily increased their body weight and β‐cell mass, as well as insulin and glucose levels compared to the DR rats. HE feeding affected both DIO and DR rats leading to an increased body weight and an increased β‐cell mass. Interestingly, although the β‐cell mass in DR rats and chow‐fed DIO rats appeared to constantly increase with age, the β‐cell mass in the HE‐fed DIO rats did not continue to do so. This might constitute part of an explanation for their reduced glucose tolerance. Collectively, the data support the use of HE‐fed DIO rats as a model of human obesity and insulin resistance, and accentuate its relevance for studies examining the benefit of pharmaceutical compounds targeting this disease complex.     

Comparison of the obesity phenotypes related to monosodium glutamate effect on arcuate nucleus and/or the high fat diet feeding in C57BL/6 and NMRI mice

In this study, susceptibility of inbred C57BL/6 and outbred NMRI mice to monosodium glutamate (MSG) obesity or diet-induced obesity (DIO) was compared in terms of food intake, body weight, adiposity as well as leptin, insulin and glucose levels. MSG obesity is an early-onset obesity resulting from MSG-induced lesions in arcuate nucleus to neonatal mice. Both male and female C57BL/6 and NMRI mice with MSG obesity did not differ in body weight from their lean controls, but had dramatically increased fat to body weight ratio. All MSG obese mice developed severe hyperleptinemia, more remarkable in females, but only NMRI male mice showed massive hyperinsulinemia and an extremely high HOMA index that pointed to development of insulin resistance. Diet-induced obesity is a late-onset obesity; it developed during 16-week-long feeding with high-fat diet containing 60 % calories as fat. Inbred C57BL/6 mice, which are frequently used in DIO studies, both male and female, had significantly increased fat to body weight ratio and leptin and glucose levels compared with their appropriate lean controls, but only female C57BL/6 mice had also significantly elevated body weight and insulin level. NMRI mice were less prone to DIO than C57BL/6 ones and did not show significant changes in metabolic parameters after feeding with high-fat diet.     

Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet‐induced obesity

Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high‐fat diet‐induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil‐ and macrophage‐based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi‐infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high‐fat diet, toll‐like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow‐derived macrophages from obese, B. burgdorferi‐infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice.     

Effect of 1‐methyl‐D‐tryptophan and adoptive transfer of dendritic cells on polymicrobial sepsis induced by cecal content injection

A mouse model of polymicrobial sepsis induced by cecal content injection (CCI) was developed with the aim of gaining a better understanding of the mechanism of sepsis. This model has a similar survival pattern to the conventional model with the added benefits of ability to vary the severity of sepsis and greater consistency. Administration of 1‐methyl‐D ‐tryptophan (1‐MT) to inhibit indoleamine 2,3‐dioxygenase (IDO) in mice with CCI‐induced sepsis increased the survival rate and tended to up‐regulate IL‐10/IL‐12 serum concentrations. The effectiveness of 1‐MT was confirmed by increases in IL‐10 over IL‐12 in bone marrow‐derived dendritic cells (BMDCs) treated with LPS and 1‐MT and a superior survival rate 24 hr after injection of these double treated BMDCs in the CCI‐induced sepsis model. Therefore, CCI is both a useful and reliable technique for investigating polymicrobial sepsis. The present findings using this newly developed model suggest that inhibition of IDO alleviates the severity of polymicrobial sepsis and modulates the immune response even in cases of severe systemic septic inflammation.     

Effects of Pravastatin on Obesity,Diabetes, and Adiponectin in Diet‐induced Obese Mice

Objective: The aim of this study was to investigate the in vivo effects of pravastatin on the development of obesity and diabetes in diet‐induced obese (DIO) mice. Methods and Procedures: We examined food intake, body‐weight changes, visceral white adipose tissue (WAT) adiponectin and resistin levels, and energy metabolism. Results: Treatment with 100 mg/kg/day pravastatin for 28 days decreased diet‐induced weight gain and visceral adiposity. In addition, the weight of the WAT, the triglyceride (TG) contents of the liver and muscles, and the levels of serum insulin improved in the pravastatin‐treated DIO mice. Furthermore, pravastatin treatment changed the WAT adiponectin and resistin mRNA expression and serum levels compared with the controls. Finally, pravastatin treatment increased oxygen consumption and decreased the respiratory quotient (RQ). Discussion: Pravastatin treatment prevents the development of obesity and diabetes in DIO mice. The prevention of obesity may be mediated by increased oxygen consumption and a decrease in the RQ. These results provide novel insights into the use of pravastatin as a therapeutic tool for metabolic syndromes.     

Assessment of diet-induced obese rats as an obesity model by comparative functional genomics

Objective: We applied a comparative functional genomics approach to evaluate whether diet‐induced obese (DIO) rats serve as an effective obesity model. Methods and Procedures: Gene‐expression profiles of epididymal fat from DIO and lean rats were generated using microarrays and compared with the published array data of obese and non‐obese human subcutaneous adipocytes. Results: Caloric intake and fuel efficiency were significantly higher in DIO rats, which resulted in increased body weight and adiposity. Circulating glucose, cholesterol, triglyceride, insulin, and leptin levels in DIO rats were significantly higher than those in the lean controls. DIO rats also exhibited impaired insulin sensitivity. A direct comparison of gene‐expression profiles from DIO and lean rats and those from obese and non‐obese humans revealed that global gene‐expression patterns in DIO rat fat resemble those of obese human adipocytes. Differentially expressed genes between obese and non‐obese subjects in both human and rat studies were identified and associated with biological pathways by mapping genes to Gene Ontology (GO) categories. Immune response–related genes and angiogenesis‐related genes exhibited significant upregulation in both obese humans and DIO rats when compared with non‐obese controls. However, genes in fatty acid metabolism and oxidation exhibited a broad downregulation only in obese human adipocytes but not in DIO rat epididymal fat. Discussion: Our study based on gene‐expression profiling suggested that DIO rats in general represent an appropriate obesity model. However, the discrepancies in gene‐expression alterations between DIO rats and obese humans, particularly in the metabolic pathways, may explain the limitations of using DIO rodent models in obesity research and drug discovery.     

Beneficial effect of oral administration of Lactobacillus casei strain Shirota on insulin resistance in diet-induced obesity mice

Aims: This study aimed at determining whether oral administration of a probiotic strain, Lactobacillus casei strain Shirota (LcS), can improve insulin resistance, which is the underlying cause of obesity‐associated metabolic abnormalities, in diet‐induced obesity (DIO) mice. Methods and Results: DIO mice were fed a high‐fat diet without or with 0·05% LcS for 4 weeks and then subjected to an insulin tolerance test (ITT) or oral glucose tolerance test (OGTT). Oral administration of LcS not only accelerated the reduction in plasma glucose levels during the ITT, but also reduced the elevation of plasma glucose levels during the OGTT. In addition, plasma levels of lipopolysaccharide‐binding protein (LBP), which is a marker of endotoxaemia, were augmented in the murine models of obese DIO, ob/ob, db/db and KK‐A^y and compared to those of lean mice. LcS treatment suppressed the elevation of plasma LBP levels in DIO mice, but did not affect intra‐abdominal fat weight. Conclusions: LcS improves insulin resistance and glucose intolerance in DIO mice. The reduction in endotoxaemia, but not intra‐abdominal fat, may contribute to the beneficial effects of LcS. Significance and Impact of the Study: This study suggests that LcS has the potential to prevent obesity‐associated metabolic abnormalities by improving insulin resistance.     

Orally administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune responses and intestinal microbiota of diet-induced obese mice

Aims: To investigate the influence of heat‐killed Lactobacillus gasseri TMC0356 on changes in respiratory immune function and intestinal microbiota in a diet‐induced obese mouse model. Methods and Results: Male C57BL/6J mice were fed a high‐fat diet for 16 weeks. After 8 weeks, the high‐fat‐diet‐induced obese mice (DIO mice) were randomly divided into two 0067roups, the DIO and DIO0356 groups. DIO0356 group mice were orally fed with heat‐killed TMC0356 every day for 8 weeks, while DIO group mice were exposed to 0·85% NaCl over the same time period as controls. After intervention, the pulmonary mRNA expression of cytokines and other immune molecules in DIO0356 mice compared to those in DIO group mice was significantly increased (P < 0·05, P < 0·01). In faecal bacterial profiles, analysed using the terminal restriction fragment length polymorphism (T‐RFLP) method, T‐RFLP patterns in 75% of the DIO0356 group mice were apparently changed compared with those in control group mice. Conclusion: These results suggest that inactive lactobacilli may stimulate the respiratory immune responses of obese host animals to enhance their natural defences against respiratory infection, partially associating with their potent impact on intestinal microbiota. Significance and Impact of the Study: We have demonstrated that oral administration of inactive lactobacilli may protect host animals from the lung immune dysfunction caused by obesity.     

A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.     

Meal Pattern Analysis of Diet‐Induced Obesity in Susceptible and Resistant Rats

Objective: To characterize the meal patterns of free feeding Sprague‐Dawley rats that become obese or resist obesity when chronically fed a high‐fat diet. Research Methods and Procedures: Male Sprague‐Dawley rats (N = 120) were weaned onto a high‐fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet‐induced obese (DIO)] and lower [diet‐resistant (DR)] deciles for body‐weight gain were selected for study. A cohort of chow‐fed (CF) rats weight‐matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system. Results: DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups. Discussion: The hyperphagia of a Sprague‐Dawley rat model of chronic diet‐induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.     

Hematological and acute-phase responses to diet-induced obesity in IL-6 KO mice

Obesity is associated with chronic inflammation and elevated levels of IL-6. The role of IL-6 in induction of acute-phase proteins and modulation of hematological responses has been demonstrated in models of inflammation and aging, but not in obesity. We hypothesized that IL-6 is necessary to regulate the acute-phase response and hematological changes associated with diet-induced obesity (DIO) in mice. Feeding a 60%kcal/fat diet for 13 weeks to C57BL6 WT male mice induced a significant increase in IL-6 expression in visceral adipose tissue (VAT), but not liver, compared to mice fed chow diet. Significantly elevated IL-6 levels were present in the peritoneal lavage fluid, but not plasma, of DIO compared to lean mice. A comparable degree of obesity, hepatomegaly, hyperleptinemia, VAT inflammation and insulin resistance was observed in DIO WT and IL-6 KO mice compared to WT and KO mice fed chow diet. Significant leukocytosis was observed in DIO WT but not DIO KO mice compared to lean groups. A significant reduction in platelet counts, without alterations in platelet size, percentage of circulating reticulated platelets and number of bone marrow megakaryocytes, was present in DIO KO mice compared to each other group. Hepatic expression of thrombopoietin was comparable in each group, with DIO WT and KO mice having reduced VAT expression compared to lean mice. Lean KO mice had significantly elevated plasma levels of thrombopoietin compared to each other group, whereas liver-associated thrombopoietin levels were comparable in each group. Deficiency of IL-6 resulted in blunted hepatic induction of the acute-phase protein serum amyloid A-1, whereas expression of hepcidin-1 and -2, LPS-binding protein, ceruloplasmin, plasminogen activator inhibitor-1 and thrombospondin-1 was IL-6-independent. In conclusion, in the absence of overt metabolic alterations, IL-6 modulates leukocytosis, thrombopoiesis and induction of SAA-1, but not other acute-phase proteins in obese mice.     

Obesity potentiates development of fatty liver and insulin resistance, but not atherosclerosis, in high-fat diet-fed agouti LDLR-deficient mice

Obesity is increasing at an alarming rate, and its related disorders are placing a considerable strain on our healthcare system. Although they are not always coincident, obesity is often accompanied by hyperlipidemia. Both obesity and hyperlipidemia are independently associated with atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR). Thus, we sought to determine the relative contributions of obesity and hyperlipidemia to these associated pathologies. Obese agouti (A(y)/a) mice and their littermate controls (a/a) were placed on an LDL receptor (LDLR)(-/-) background. At 4 mo of age, mice were either maintained on chow diet (CD) or placed on Western diet (WD) for 12 wk. These genetic and dietary manipulations yielded four experimental groups: 1) lean, a/a;LDLR(-/-)CD; 2) genetic-induced obesity (GIO), A(y)/a;LDLR(-/-)CD; 3) diet-induced obesity (DIO), a/a;LDLR(-/-)WD; and 4) genetic- plus diet-induced obesity (GIO/DIO), A(y)/a;LDLR(-/-)WD. Lipoprotein profiles revealed increased VLDL and LDL particles in WD-fed mice compared with CD-fed controls. The hyperlipidemia present in this mouse model was the result of both increased hepatic triglyceride production and delayed lipoprotein clearance from the plasma. Both WD-fed groups exhibited similar levels of atherosclerotic lesion area, with increased obesity in the GIO/DIO group having no impact on atherogenesis. However, the severe obesity in the GIO/DIO group did aggravate NAFLD and IR. These findings suggest that, although obesity and hyperlipidemia exert individual pathological effects, the combination of the two has the potential to exert an additive effect on NAFLD and IR but not atherosclerosis in this mouse model.     

Food Intake‐independent Effects of CB1 Antagonism on Glucose and Lipid Metabolism

Overactivity of the endocannabinoid system (ECS) has been linked to abdominal obesity and other risk factors for cardiovascular disease and type 2 diabetes. Conversely, administration of cannabinoid receptor type 1 (CB1) antagonists reduces adiposity in obese animals and humans. This effect is only in part secondary to the anorectic action of CB1 agonists. In order to assess the actions of CB1 antagonism on glucose homeostasis, diet‐induced obese (DIO) rats received the CB1 antagonist rimonabant (10 mg/kg, intraperitoneally (IP)) or its vehicle for 4 weeks, or were pair‐fed to the rimonabant‐treated group for the same length of time. Rimonabant treatment transiently reduced food intake, while inducing body weight loss throughout the study. Rats receiving rimonabant had significantly less body fat and circulating leptin compared to both vehicle and pair‐fed groups. Rimonabant, but not pair‐feeding, also significantly decreased circulating nonesterified fatty acid (NEFA) and triacylglycerol (TG) levels, and reduced TG content in oxidative skeletal muscle. Although no effects were observed during a glucose tolerance test (GTT), rimonabant restored insulin sensitivity to that of chow‐fed, lean controls during an insulin tolerance test (ITT). Conversely, a single dose of rimonabant to DIO rats had no acute effect on insulin sensitivity. These findings suggest that in diet‐induced obesity, chronic CB1 antagonism causes weight loss and improves insulin sensitivity by diverting lipids from storage toward utilization. These effects are independent of the anorectic action of the drug.