Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell-deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue-resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue-resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.
Peroxisome proliferator-activated receptor ␣ (PPAR␣) is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically by using high-affinity synthetic agonists. Here we initially set out to elucidate the similarities in gene induction between Wy14643 and fasting. Numerous genes were commonly regulated in liver between the two treatments, including many classical PPAR␣ target genes, such as Aldh3a2 and Cpt2. Remarkably, several genes induced by Wy14643 were upregulated by fasting independently of PPAR␣, including Lpin2 and St3gal5, suggesting involvement of another transcription factor. Using chromatin immunoprecipitation, Lpin2 and St3gal5 were shown to be direct targets of PPAR/␦ during fasting, whereas Aldh3a2 and Cpt2 were exclusive targets of PPAR␣. Binding of PPAR/␦ to the Lpin2 and St3gal5 genes followed the plasma free fatty acid (FFA) concentration, consistent with activation of PPAR/␦ by plasma FFAs. Subsequent experiments using transgenic and knockout mice for Angptl4, a potent stimulant of adipose tissue lipolysis, confirmed the stimulatory effect of plasma FFAs on Lpin2 and St3gal5 expression levels via PPAR/␦. In contrast, the data did not support activation of PPAR␣ by plasma FFAs. The results identify Lpin2 and St3gal5 as novel PPAR/␦ target genes and show that upregulation of gene expression by PPAR/␦ is sensitive to plasma FFA levels. In contrast, this is not the case for PPAR␣, revealing a novel mechanism for functional differentiation between PPARs.Hepatic lipid metabolism is governed by a complex interplay between hormones, transcription factors, and energy substrates, allowing for rapid adaptations to changes in metabolic needs (21). According to the traditional view, energy substrates such as fatty acids influence lipid metabolism by promoting flux through a particular pathway via mass action. However, it has become clear that energy substrates can also directly govern the transcription of enzymes involved in lipid metabolism via mechanisms analogous to those of many hormones. Indeed, it is now evident that glucose and fatty acids play a major regulatory role in hepatic lipid metabolism via direct activation or inhibition of specific transcription factors, including carbohydrate response element binding protein (6, 63), sterol response element binding protein 1 (SREBP1) (2, 41, 58, 61, 62), and peroxisome proliferator-activated receptor ␣ (PPAR␣) (38).Although numerous transcription factors have been shown to be activated by fatty acids in vitro, recent data suggest that PPAR␣ is dominant in mediating the effects of dietary fatty acids on gene expression in liver (48). PPAR␣ is a member of the superfamily of nuclear receptors and is closely related to the other PPAR isoforms, /␦ and ␥ (32). Similar to several other nuclear receptors, PPARs function as heterodimers with the retinoid X receptor and bind to specific sequences on the DNA referred to as PPAR response elements (PPREs) (8,11,26). Numerous studies have shown that fatty acids...
BackgroundThe effect of dietary fats on human health and disease are likely mediated by changes in gene expression. Several transcription factors have been shown to respond to fatty acids, including SREBP-1c, NF-κB, RXRs, LXRs, FXR, HNF4α, and PPARs. However, it is unclear to what extent these transcription factors play a role in gene regulation by dietary fatty acids in vivo.Methodology/Principal FindingsHere, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid in combination with gene expression profiling to examine the effects of various individual dietary fatty acids on hepatic gene expression in mice. We observed that the number of significantly changed genes and the fold-induction of genes increased with increasing fatty acid chain length and degree of unsaturation. Importantly, almost every single gene regulated by dietary unsaturated fatty acids remained unaltered in mice lacking PPARα. In addition, the majority of genes regulated by unsaturated fatty acids, especially docosahexaenoic acid, were also regulated by the specific PPARα agonist WY14643. Excellent agreement was found between the effects of unsaturated fatty acids on mouse liver versus cultured rat hepatoma cells. Interestingly, using Nuclear Receptor PamChip® Arrays, fatty acid- and WY14643-induced interactions between PPARα and coregulators were found to be highly similar, although several PPARα-coactivator interactions specific for WY14643 were identified.Conclusions/SignificanceWe conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARα and mimic those of synthetic PPARα agonists in terms of regulation of target genes and molecular mechanism. Use of synthetic dietary triglycerides may provide a novel paradigm for nutrigenomics research.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.