The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα is activated by fatty acids and various other lipid ...species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver. Here, an overview is provided of the role and regulation of PPARα in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARα in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARα activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARα. 6) In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes.
•The level of PPARA mRNA expression in human and mouse liver is similar.•PPARA expression in human liver is reduced in non-alcoholic steatohepatitis.•PPARα in human liver effectively induces numerous genes involved in lipid metabolism.•PPARα in human liver represses numerous genes involved in immunity-related pathways.•Peroxisome proliferators do not promote tumour formation in human liver.
Dit artikel is gebaseerd op de NDF-nascholing en het artikel dat Jaap Kroon, stafarts diabetes PoZoB, Nicolaas Schaper, emeritus hoogleraar endocrinologie en (diabetes)podotherapeut Lian ...Stoeldraaijers hebben gepubliceerd in Huisarts en Wetenschap. De informatie is met hun toestemming overgenomen. Zie: Kroon J, Schaper N, Stoeldraaijers L., "Eerste hulp bij een diabetisch voetulcus", H&W 2021;64(3):53-8.
Aims/hypothesis
Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and ...trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions.
Methods
F4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific
Hif1α
−/−
mice was used to examine the role of hypoxia-inducible factor-1α (HIF-1α) in ATMs part of obese adipose tissue. In vitro, bone marrow-derived macrophages were co-cultured with adipose tissue explants to examine adipose tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production.
Results
Transcriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14
+
cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed macrophages. Instead, metabolic activation of macrophages was dose-dependently induced by a set of adipose tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean adipose tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of macrophages in obese adipose tissue. HIF-1α, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity.
Conclusions/interpretation
Our results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity.
Data availability
Microarray data of ATMs isolated from obese or lean mice have been submitted to the Gene Expression Omnibus (accession no. GSE84000).
Renewed interest in immune cell metabolism has led to the emergence of a research field aimed at studying the importance of metabolic processes for an effective immune response. In addition to the ...adaptive immune system, cells of the myeloid lineage have been shown to undergo robust metabolic changes upon activation. Whereas the specific metabolic requirements of myeloid cells after lipopolysaccharide/TLR4 stimulation have been extensively studied, recent evidence suggested that this model does not represent a metabolic blueprint for activated myeloid cells. Instead, different microbial stimuli, pathogens, or tissue microenvironments lead to specific and complex metabolic rewiring of myeloid cells. Here we present an overview of the metabolic heterogeneity in activated myeloid cells during health and disease. Directions for future research are suggested to ultimately provide new therapeutic opportunities. The uniqueness of metabolic signatures accompanying different conditions will require tailor-made interventions to ultimately modulate aberrant myeloid cell activation during disease.
The importance of intracellular metabolism in determining myeloid cell function has rapidly gained interest. In this review, Stienstra et al. discuss the current state of knowledge in the field of immunometabolism, revealing specific and complex metabolic rewiring in activated myeloid cells in health and disease.
•Cytokines of the IL-1 family play an important role in metabolic inflammation.•The development of obesity affects IL-1α, IL-1β, IL-1Ra, IL-18, IL-33 and IL-37 activity.•IL-1α, IL-1β, IL-1Ra, IL-18, ...IL-33 and IL-37 alter insulin signaling routes.•The IL-1 family of cytokines holds multiple targets to combat metabolic diseases.
Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes.
In response to inflammatory activation by pathogens, macrophages accumulate triglycerides in intracellular lipid droplets. The mechanisms underlying triglyceride accumulation and its exact role in ...the inflammatory response of macrophages are not fully understood. Here, we aim to further elucidate the mechanism and function of triglyceride accumulation in the inflammatory response of activated macrophages. Lipopolysaccharide (LPS)-mediated activation markedly increased triglyceride accumulation in macrophages. This increase could be attributed to up-regulation of the hypoxia-inducible lipid droplet–associated (HILPDA) protein, which down-regulated adipose triglyceride lipase (ATGL) protein levels, in turn leading to decreased ATGL-mediated triglyceride hydrolysis. The reduction in ATGL-mediated lipolysis attenuated the inflammatory response in macrophages after ex vivo and in vitro activation, and was accompanied by decreased production of prostaglandin-E2 (PGE2) and interleukin-6 (IL-6). Overall, we provide evidence that LPS-mediated activation of macrophages suppresses lipolysis via induction of HILPDA, thereby reducing the availability of proinflammatory lipid precursors and suppressing the production of PGE2 and IL-6.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in ...NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.
Inflammation originating from the adipose tissue is considered to be one of the main driving forces for the development of insulin resistance and type 2 diabetes in obese individuals. Although a ...plethora of different immune cells shapes adipose tissue inflammation, this review is specifically focused on the contribution of macrophages that reside in adipose tissue in lean and obese conditions. Both conventional and tissue-specific functions of adipose tissue macrophages (ATMs) in lean and obese adipose tissue are discussed and linked with metabolic and inflammatory changes that occur during the development of obesity. Furthermore, we will address various circulating and adipose tissue-derived triggers that may be involved in shaping the ATM phenotype and underlie ATM function in lean and obese conditions. Finally, we will highlight how these changes affect adipose tissue inflammation and may be targeted for therapeutic interventions to improve insulin sensitivity in obese individuals.
Highlights
• Macrophages play a significant role in regulating adipose tissue functioning during health and disease
• In addition to conventional functions such as clearing cellular debris and participating in tissue immune surveillance, lipid buffering is an important function of ATMs
• Obesity-induced inflammation, characterised by an elevated number of proinflammatory macrophages in adipose tissue, has been suggested to contribute to systemic insulin resistance
• Their origin, as well as a combination of peripheral changes and adipose tissue-derived stressors, probably contribute to ATM dysfunction and inflammatory traits during obesity
• Identification of transcriptional differences between ATMs from lean vs obese adipose tissue at several key points during the development of obesity and insulin resistance may reveal upstream triggers, regulatory factors and intracellular pathways that shape ATM function
• Targeting metabolic capacity rather than the inflammatory phenotype of ATMs may hold potential to restore ATM function and adipose tissue homeostasis in obese individuals
In addition to high-fat diet (HFD) and inactivity, inflammation and microbiota composition contribute to obesity. Inhibitory immune receptors, such as NLRP12, dampen inflammation and are important ...for resolving inflammation, but their role in obesity is unknown. We show that obesity in humans correlates with reduced expression of adipose tissue NLRP12. Similarly, Nlrp12−/− mice show increased weight gain, adipose deposition, blood glucose, NF-κB/MAPK activation, and M1-macrophage polarization. Additionally, NLRP12 is required to mitigate HFD-induced inflammasome activation. Co-housing with wild-type animals, antibiotic treatment, or germ-free condition was sufficient to restrain inflammation, obesity, and insulin tolerance in Nlrp12−/− mice, implicating the microbiota. HFD-fed Nlrp12−/− mice display dysbiosis marked by increased obesity-associated Erysipelotrichaceae, but reduced Lachnospiraceae family and the associated enzymes required for short-chain fatty acid (SCFA) synthesis. Lachnospiraceae or SCFA administration attenuates obesity, inflammation, and dysbiosis. These findings reveal that Nlrp12 reduces HFD-induced obesity by maintaining beneficial microbiota.
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•NLRP12 expression is reduced in the adipose tissue of humans with increased obesity•Nlrp12−/− mice show increased weight gain and adipose tissue inflammation•Nlrp12-mediated protection from obesity and inflammation is microbiota dependent•Lachnospiraceae and short-chain fatty acids mitigate obesity and insulin resistance
Truax et al. show that myeloid-expressed NLRP12 restrains high-fat-diet-induced obesity and type 2 diabetes by attenuating TNF, IL-6, NF-kB, MAPK, M1-macrophage polarization, and inflammasome activation in adipose tissue. This protective function of NLRP12 is microbiota dependent, and is associated with Lachnospiraceae and their metabolites, which mitigate obesity.
Autophagy is a lysosomal degradation pathway recycling intracellular long-lived proteins and damaged organelles, thereby maintaining cellular homeostasis. In addition to inflammatory processes, ...autophagy has been implicated in the regulation of adipose tissue and beta cell functions. In obesity and type 2 diabetes autophagic activity is modulated in a tissue-dependent manner. In this review we discuss the regulation of autophagy in adipose tissue and beta cells, exemplifying tissue-specific dysregulation of autophagy and its implications for the pathophysiology of obesity and type 2 diabetes. We will highlight common themes and outstanding gaps in our understanding, which need to be addressed before autophagy could be envisioned as a therapeutic target for the treatment of obesity and diabetes.
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