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Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell-derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.

Elevations in fructose consumption have been reported to contribute significantly to an increased incidence of obesity and metabolic diseases in industrial countries. Mechanistically, a high fructose intake leads to the dysregulation of glucose, triglyceride, and cholesterol metabolism in the liver, and causes elevations in inflammation and drives the progression of nonalcoholic fatty liver disease (NAFLD). A high fructose consumption is considered to be toxic to the body, and there are ongoing measures to develop pharmaceutical therapies targeting fructose metabolism. Although a large amount of work has summarized the effects fructose exposure within the intestine, liver, and kidney, there remains a gap in our knowledge regarding how fructose both indirectly and directly influences immune cell recruitment, activation, and function in metabolic tissues, which are essential to tissue and systemic inflammation. The most recent literature demonstrates that direct fructose exposure regulates oxidative metabolism in macrophages, leading to inflammation. The present review highlights (1) the mechanisms by which fructose metabolism impacts crosstalk between tissues, nonparenchymal cells, microbes, and immune cells; (2) the direct impact of fructose on immune cell metabolism and function; and (3) therapeutic targets of fructose metabolism to treat NAFLD. In addition, the review highlights how fructose disrupts liver tissue homeostasis and identifies new therapeutic targets for treating NAFLD and obesity. [ABSTRACT FROM AUTHOR]

Background & aims: Activated CD8+ T cells are elevated in Nonalcoholic steatohepatitis (NASH) and are important for driving fibrosis and inflammation. Despite this, mechanisms of CD8+ T cell activation in NASH are largely limited. Specific CD8+ T cell subsets may become activated through metabolic signals or cytokines. However, studies in NASH have not evaluated the impact of antigen presentation or the involvement of specific antigens. Therefore, we determined if activated CD8+ T cells are dependent on MHC class I expression in NASH to regulate fibrosis and inflammation. Methods: We used H2Kb and H2Db deficient (MHC I KO), Kb transgenic mice, and myeloid cell Kb deficient mice (LysM Kb KO) to investigate how MHC class I impacts CD8+ T cell function and NASH. Flow cytometry, gene expression, and histology were used to examine hepatic inflammation and fibrosis. The hepatic class I immunopeptidome was evaluated by mass spectrometry. Results: In NASH, MHC class I isoform H2Kb was upregulated in myeloid cells. MHC I KO demonstrated protective effects against NASH-induced inflammation and fibrosis. Kb mice exhibited increased fibrosis in the absence of H2Db while LysM Kb KO mice showed protection against fibrosis but not inflammation. H2Kb restricted peptides identified a unique NASH peptide Ncf2 capable of CD8+ T cell activation in vitro. The Ncf2 peptide was not detected during fibrosis resolution. Conclusion: These results suggest that activated hepatic CD8+ T cells are dependent on myeloid cell MHC class I expression in diet induced NASH to promote inflammation and fibrosis. Additionally, our studies suggest a role of NADPH oxidase in the production of Ncf2 peptide generation. [ABSTRACT FROM AUTHOR]

Obesity-associated inflammation is characterized by recruitment of macrophages (M[phi]) into white adipose tissue (WAT) and production of inflammatory cytokines, leading to the development of insulin resistance. The xanthones, [alpha]- and [gamma]-mangostin (MG), are major bioactive compounds found in mangosteen that are reported to have antiinflammatory and antioxidant properties. Thus, we examined the efficacy of MG to prevent lipopolysaccharide (LPS)-mediated inflammation in human M[phi] (differentiated U937 cells) and cross-talk with primary cultures of newly differentiated human adipocytes. We found that [alpha]- and [gamma]-MG attenuated LPS-induced expression of inflammatory genes, including tumor necrosis factor-[alpha], interleukin-6, and interferon [gamma]-inducible protein-10 in a dose-dependent manner in M[phi]. We also found that [alpha]- and [gamma]-MG attenuated LPS-activated mitogen-activated protein kinases (MAPK) and activator protein (AP)-1, but only [gamma]-MG reduced nuclear factor-[kappa]B (NF-[kappa]B). In addition, [alpha]- and [gamma]-MG attenuated LPS suppression of PPAR[gamma]/gene expression in a dose-dependent manner. Notably, the ability of M[phi]-conditioned media to cause inflammation and insulin resistance in primary cultures of human adipocytes was attenuated by pretreating M[phi] with [gamma]-MG. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation in M[phi] and insulin resistance in adipocytes, possibly by preventing the activation of MAPK, NF-[kappa]B, and AP-1, which are central to inflammatory cytokine production in WAT. doi: 10.3945/jn.109.120022

The xanthones, [alpha]- and [gamma]-mangostin (MG), are major bioactive compounds found in mangosteen and are reported to have antiinflammatory properties in several murine models. Given the association between obesity, chronic low-grade inflammation, and insulin resistance, we examined the effects of [alpha]- and [gamma]-MG on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with lipopolysaccharide (LPS). [alpha]-and [gamma]-MG decreased the induction by LPS of inflammatory genes, including tumor necrosis factor-[alpha], interleukin (IL)-1[beta], IL-6, IL-8, monocyte chemoattractant protein-1, and Toll-like receptor-2. Moreover, [alpha]-and [gamma]-MG attenuated LPS activation of the mitogen-activated protein kinases (MAPK) c-jun N[H.sub.2]-terminal kinase, extracellular signal-related kinase, and p38. [alpha]-and [gamma]-MG also attenuated LPS activation of c-Jun and activator protein (AP)-1 activity. [gamma]-MG was more effective than [alpha]-MG on an equimolar basis. Furthermore, [gamma]-MG but not [alpha]-MG attenuated LPS-mediated I[kappa]B-[alpha] degradation and nuclear factor-[kappa]B (NF-[kappa]B) activity. In addition, [gamma]-MG prevented the suppression by LPS of insulin-stimulated glucose uptake and PPAR- [gamma], and adiponectin gene expression. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation and insulin resistance in human adipocytes, possibly by inhibiting the activation of MAPK, NF-[kappa]B, and AP-1.

This review highlights the inflammatory and insulin-antagonizing effects of saturated fatty acids (SFA), which contribute to the development of metabolic syndrome. Mechanisms responsible for these unhealthy effects of SFA include: 1) accumulation of diacylglycerol and ceramide; 2) activation of nuclear factor-[kappa]B, protein kinase C-[theta], and mitogen-activated protein kinases, and subsequent induction of inflammatory genes in white adipose tissue, immune cells, and myotubes; 3) decreased PPAR[gamma], coactivator-1 [alpha]/[beta] activation and adiponectin production, which decreases the oxidation of glucose and fatty acids (FA); and 4) recruitment of immune cells like macrophages, neutrophils, and bone marrow-derived dendritic cells to WAT and muscle. Several studies have demonstrated potential health benefits of substituting SFA with unsaturated FA, particularly oleic acid and (n-3) FA. Thus, reducing consumption of foods rich in SFA and increasing consumption of whole grains, fruits, vegetables, lean meats and poultry, fish, low-fat dairy products, and oils containing oleic acid or (n-3) FA is likely to reduce the incidence of metabolic disease.

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 PPAR[gamma] target gene expression. We hypothesized that CLA antagonizes the activity of PPAR[gamma] in an isomer-specific 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 PPAR[gamma] by 10,12 CLA was accompanied by an increase in PPAR[gamma] and extracellular signal-related kinase (ERK) 1/2 phosphorylation, followed by decreased PPAR[gamma], protein levels. To investigate if 10,12 CLA-mediated delipidation was preventable with a PPAR[gamma] 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 PPAR[gamma] 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 PPAR[gamma] target genes. However, the levels of PPAR[gamma] 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 ligand-dependent PPAR[gamma] activity, possibly via PPAR[gamma] phosphorylation by ERK.

Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell-derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8+ T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8+ T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8+ T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8+ T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8+ T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8+ T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8+ T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8+ T cells may be a novel approach for treatment of obesity-associated NASH. [ABSTRACT FROM AUTHOR]

Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess free fatty acids and regulation of the extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFehi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron-handling genes. Although studies have demonstrated that iron homeostasis is important for adipocyte health, little is known about how MFehi ATMs may respond to and influence adipose tissue iron availability. Two methodologies were used to address this question: dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFehi ATMs accumulated excess iron, whereas the iron content of MFelo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFehi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFehi ATMs incorporated high levels of iron, and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFehi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFelo ATM incorporation into the MFehi pool. The MFehi ATM population maintained its low inflammatory profile and iron-cycling expression profile. These studies expand the field's understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload. [ABSTRACT FROM AUTHOR]