The antiobesity mechanism of conjugated linoleic acid

Given the steady rise in obesity worldwide, it is important to identify dietary compounds that prevent adiposity. One dietary strategy is supplementation with conjugated linoleic acid (CLA), which has been demonstrated to reduce body fat mass. However, side effects associated with CLA supplementation include inflammation, insulin resistance, and dyslipidemia. Elucidation of the antiobesity mechanism of CLA is critical for evaluating its efficacy and safety as a dietary supplement for treating obesity. Therefore, this research examined the upstream mechanism by which CLA induced inflammation, insulin resistance, and delipidation of human adipocytes. Our research group has previously demonstrated that trans-10, cis-12 (10,12) CLA causes delipidation of human adipocytes via activating nuclear factor kappa B (NF?B) and mitogen-activated protein kinase / extracellular signal-regulated kinase kinase (MEK/ERK) signaling, leading to inflammation and the suppression of peroxisome proliferator activated receptor (PPAR?) and decreased glucose and fatty acid uptake. Based on these findings, the following questions were addressed using primary cultures of newly differentiated human adipocytes as a cell model 1) How does CLA impact PPAR? activity?, 2) What upstream mechanisms activate ERK, NF?B and induce inflammation?, and 3) Does resveratrol, a phenolic phytochemical with antioxidant properties, attenuate CLA-induced inflammation, insulin resistance, and delipidation? Answers to these questions were as follows. 1) 10,12 CLA antagonized ligand-dependent PPAR? activity, possibly via PPAR? phosphorylation by ERK. 10,12 CLA suppression of PPAR? and insulin-stimulated glucose uptake, along with delipidation were partially rescued by co-supplementation with the PPAR? agonist BRL, further supporting CLA antagonizing PPAR?. 2) Cultures treated with TMB-8, an inhibitor of calcium release from the endoplasmic reticulum or KN-62, an inhibitor of calcium/calmodulin-dependent kinase II (CAMKII) attenuated 10,12 CLA-mediated reactive oxygen species (ROS) production, mitogen-activated protein kinase (MAPK) activation, inflammatory gene induction, and insulin resistance. These data suggested that 10,12 CLA-mediated inflammation and insulin resistance are dependent on calcium release from the endoplasmic reticulum or CAMKII. 3) Treatment with resveratrol prevented 10,12 CLA-mediated inflammation and insulin resistance by attenuating intracellular calcium, ROS, and inflammation, by increasing PPAR? activity. Collectively, these data suggest that one of the antiobesity mechanisms of 10,12 CLA is inducing cellular stress and inflammation which antagonize PPAR?, leading to insulin resistance and delipidation of human adipocytes

Impact of Macrophage Inflammatory Protein-1α Deficiency on Atherosclerotic Lesion Formation, Hepatic Steatosis, and Adipose Tissue Expansion

Macrophage inflammatory protein-1α (CCL3) plays a well-known role in infectious and viral diseases; however, its contribution to atherosclerotic lesion formation and lipid metabolism has not been determined. Low density lipoprotein receptor deficient (LDLR−/−) mice were transplanted with bone marrow from CCL3−/− or C57BL/6 wild type donors. After 6 and 12 weeks on western diet (WD), recipients of CCL3−/− marrow demonstrated lower plasma cholesterol and triglyceride concentrations compared to recipients of C57BL/6 marrow. Atherosclerotic lesion area was significantly lower in female CCL3−/− recipients after 6 weeks and in male CCL3−/− recipients after 12 weeks of WD feeding (P<0.05). Surprisingly, male CCL3−/− recipients had a 50% decrease in adipose tissue mass after WD-feeding, and plasma insulin, and leptin levels were also significantly lower. These results were specific to CCL3, as LDLR−/− recipients of monocyte chemoattractant protein−/− (CCL2) marrow were not protected from the metabolic consequences of high fat feeding. Despite these improvements in LDLR−/− recipients of CCL3−/− marrow in the bone marrow transplantation (BMT) model, double knockout mice, globally deficient in both proteins, did not have decreased body weight, plasma lipids, or atherosclerosis compared with LDLR−/− controls. Finally, there were no differences in myeloid progenitors or leukocyte populations, indicating that changes in body weight and plasma lipids in CCL3−/− recipients was not due to differences in hematopoiesis. Taken together, these data implicate a role for CCL3 in lipid metabolism in hyperlipidemic mice following hematopoietic reconstitution

\u3ci\u3eTrans\u3c/i\u3e-10, \u3ci\u3eCis\u3c/i\u3e-12 Conjugated Linoleic Acid Antagonizes Ligand- Dependent PPARγ Activity in Primary Cultures of Human Adipocytes

We previously demonstrated that trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) causes human adipocyte delipidation, insulin resistance, and inflammation in part by attenuating PPARγ target gene expression. We hypothesized that CLA antagonizes the activity of PPARγ in an isomerspecific manner. 10,12 CLA, but not cis-9, trans-11 (9,11) CLA, suppressed ligand-stimulated activation of a peroxisome proliferator response element-luciferase reporter. This decreased activation of PPARγ by 10,12 CLA was accompanied by an increase in PPARγ and extracellular signal-related kinase (ERK)1/2 phosphorylation, followed by decreased PPARγ protein levels. To investigate if 10,12 CLA-mediated delipidation was preventable with a PPARγ ligand (BRL), cultures were treated for 1 wk with 10,12 CLA or 10,12 CLA + BRL and adipogenic gene and protein expression, glucose uptake, and triglyceride (TG) were measured. BRL cosupplementation completely prevented 10,12 CLA suppression of adipocyte fatty acid-binding protein, lipoprotein lipase, and perilipin mRNA levels without preventing reductions in PPARγ or insulin-dependent glucose transporter 4 (GLUT4) expression, glucose uptake, or TG. Lastly, we investigated the impact of CLA withdrawal in the absence or presence of BRL for 2 wk. CLA withdrawal did not rescue CLA-mediated reductions in adipogenic gene and protein expression. In contrast, BRL supplementation for 2 wk following CLA withdrawal rescued mRNA levels of PPARγ target genes. However, the levels of PPARγ and GLUT4 protein and TG were only partially rescued by BRL. Collectively, we demonstrate for the first time, to our knowledge, that 10,12 CLA antagonizes liganddependent PPARγ activity, possibly via PPARγ phosphorylation by ERK

Mouse models of the metabolic syndrome

The metabolic syndrome (MetS) is characterized by obesity concomitant with other metabolic abnormalities such as hypertriglyceridemia, reduced high-density lipoprotein levels, elevated blood pressure and raised fasting glucose levels. The precise definition of MetS, the relationships of its metabolic features, and what initiates it, are debated. However, obesity is on the rise worldwide, and its association with these metabolic symptoms increases the risk for diabetes and cardiovascular disease (among many other diseases). Research needs to determine the mechanisms by which obesity and MetS increase the risk of disease. In light of this growing epidemic, it is imperative to develop animal models of MetS. These models will help determine the pathophysiological basis for MetS and how MetS increases the risk for other diseases. Among the various animal models available to study MetS, mice are the most commonly used for several reasons. First, there are several spontaneously occurring obese mouse strains that have been used for decades and that are very well characterized. Second, high-fat feeding studies require only months to induce MetS. Third, it is relatively easy to study the effects of single genes by developing transgenic or gene knockouts to determine the influence of a gene on MetS. For these reasons, this review will focus on the benefits and caveats of the most common mouse models of MetS. It is our hope that the reader will be able to use this review as a guide for the selection of mouse models for their own studies

Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments

Objective: Obesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness. Methods: C57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity. Results: Eosinophils were increased ∼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils. Conclusions: We have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate. : Restoring obese adipose eosinophils to lean adipose levels via rIL5 administration is not sufficient to regain metabolic fitness Author Video: Author Video Watch what authors say about their articles Keywords: Inflammation, Obesity, Diabetes, Eosinophils, Interleukin 5, Adipose tissu