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• W2112708847 abstract "Research Article9 February 2015Open Access Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance Emmanuel Denou Emmanuel Denou Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Karine Lolmède Karine Lolmède Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France Search for more papers by this author Lucile Garidou Lucile Garidou Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Celine Pomie Celine Pomie Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Chantal Chabo Chantal Chabo Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France VAIOMER SAS, Prologue Biotech, Labège, France Search for more papers by this author Trevor C Lau Trevor C Lau Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Morgan D Fullerton Morgan D Fullerton Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Department of Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Giulia Nigro Giulia Nigro Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786, Institut Pasteur, Paris, France Search for more papers by this author Alexia Zakaroff-Girard Alexia Zakaroff-Girard Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France Search for more papers by this author Elodie Luche Elodie Luche Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Céline Garret Céline Garret Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Matteo Serino Matteo Serino Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Jacques Amar Jacques Amar Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Michael Courtney Michael Courtney VAIOMER SAS, Prologue Biotech, Labège, France Search for more papers by this author Joseph F Cavallari Joseph F Cavallari Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Brandyn D Henriksbo Brandyn D Henriksbo Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Nicole G Barra Nicole G Barra Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Kevin P Foley Kevin P Foley Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Joseph B McPhee Joseph B McPhee Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Brittany M Duggan Brittany M Duggan Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Hayley M O'Neill Hayley M O'Neill Department of Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Amanda J Lee Amanda J Lee Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Philippe Sansonetti Philippe Sansonetti Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786, Institut Pasteur, Paris, France Search for more papers by this author Ali A Ashkar Ali A Ashkar Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Waliul I Khan Waliul I Khan Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada Search for more papers by this author Michael G Surette Michael G Surette Department of Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada Search for more papers by this author Anne Bouloumié Anne Bouloumié Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France Search for more papers by this author Gregory R Steinberg Gregory R Steinberg Department of Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Rémy Burcelin Corresponding Author Rémy Burcelin Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Jonathan D Schertzer Corresponding Author Jonathan D Schertzer Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Emmanuel Denou Emmanuel Denou Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Karine Lolmède Karine Lolmède Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France Search for more papers by this author Lucile Garidou Lucile Garidou Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Celine Pomie Celine Pomie Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Chantal Chabo Chantal Chabo Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France VAIOMER SAS, Prologue Biotech, Labège, France Search for more papers by this author Trevor C Lau Trevor C Lau Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Morgan D Fullerton Morgan D Fullerton Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Department of Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Giulia Nigro Giulia Nigro Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786, Institut Pasteur, Paris, France Search for more papers by this author Alexia Zakaroff-Girard Alexia Zakaroff-Girard Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France Search for more papers by this author Elodie Luche Elodie Luche Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Céline Garret Céline Garret Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Matteo Serino Matteo Serino Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Jacques Amar Jacques Amar Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Michael Courtney Michael Courtney VAIOMER SAS, Prologue Biotech, Labège, France Search for more papers by this author Joseph F Cavallari Joseph F Cavallari Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Brandyn D Henriksbo Brandyn D Henriksbo Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Nicole G Barra Nicole G Barra Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Kevin P Foley Kevin P Foley Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Joseph B McPhee Joseph B McPhee Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Brittany M Duggan Brittany M Duggan Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Hayley M O'Neill Hayley M O'Neill Department of Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Amanda J Lee Amanda J Lee Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Philippe Sansonetti Philippe Sansonetti Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786, Institut Pasteur, Paris, France Search for more papers by this author Ali A Ashkar Ali A Ashkar Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Waliul I Khan Waliul I Khan Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada Search for more papers by this author Michael G Surette Michael G Surette Department of Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada Search for more papers by this author Anne Bouloumié Anne Bouloumié Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France Search for more papers by this author Gregory R Steinberg Gregory R Steinberg Department of Medicine, McMaster University, Hamilton, ON, Canada Search for more papers by this author Rémy Burcelin Corresponding Author Rémy Burcelin Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France Search for more papers by this author Jonathan D Schertzer Corresponding Author Jonathan D Schertzer Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Search for more papers by this author Author Information Emmanuel Denou1,‡, Karine Lolmède2,3,‡, Lucile Garidou2,4, Celine Pomie2,4, Chantal Chabo2,4,5, Trevor C Lau1, Morgan D Fullerton1,6, Giulia Nigro7, Alexia Zakaroff-Girard2,3, Elodie Luche2,4, Céline Garret2,4, Matteo Serino2,4, Jacques Amar2,4, Michael Courtney5, Joseph F Cavallari1, Brandyn D Henriksbo1, Nicole G Barra8, Kevin P Foley1, Joseph B McPhee1, Brittany M Duggan1, Hayley M O'Neill6, Amanda J Lee8, Philippe Sansonetti7, Ali A Ashkar8, Waliul I Khan8,9, Michael G Surette6,9, Anne Bouloumié2,3, Gregory R Steinberg6, Rémy Burcelin 2,4 and Jonathan D Schertzer 1 1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada 2Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France 3Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France 4Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France 5VAIOMER SAS, Prologue Biotech, Labège, France 6Department of Medicine, McMaster University, Hamilton, ON, Canada 7Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786, Institut Pasteur, Paris, France 8Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada 9Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada ‡These authors contributed equally to this work *Corresponding author. Tel: +33 561 325 614; E-mail: [email protected] *Corresponding author. Tel: +1 905 525 9140 ext. 22254; Fax: +1 905 525 9033; E-mail: [email protected] EMBO Mol Med (2015)7:259-274https://doi.org/10.15252/emmm.201404169 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Pattern recognition receptors link metabolite and bacteria-derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity-promoting high-fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2−/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic-derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2−/− mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN-NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD-fed NOD2−/− mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ-free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes. Synopsis Nutritional and bacterial cues engage the immune system during the chronic inflammation associated with obesity, which could lead to insulin resistance. An intact NOD2-peptidoglycan sensing system prevents excessive dysbiosis-related inflammation and insulin resistance during obesity. NOD2 in non-hematopoietic cells protects against obesity-induced inflammation and insulin resistance. NOD2 limits accumulation of bacterial markers and inflammation of adipose and liver tissues during obesity. The microbiota of NOD2-deficient mice contributes to metabolic inflammation and insulin resistance. Introduction Obesity is associated with an elevation in the chronic inflammatory tone of metabolic tissues. This metabolic inflammation regulates glucose homeostasis, and the underlying host immune responses are emerging (Greiner & Bäckhed, 2011). Accumulation of immune cells such as neutrophils, lymphocytes, and macrophages in adipose and liver tissues during obesity are associated with augmented inflammatory mediators that contribute to insulin resistance (Weisberg et al, 2003; Elgazar-Carmon et al, 2008; Feuerer et al, 2009; Lumeng et al, 2009; Winer et al, 2009, 2011; Talukdar et al, 2012). The triggering mechanisms responsible for metabolic inflammation during obesity are ill-defined, but nutrient excess and bacterial origins have been proposed (Gregor & Hotamisligil, 2011; Nicholson et al, 2012). The ability of the gut microbiota from obese mice to predispose lean mice to increased weight gain has been linked to increased energy harvesting capacity (Turnbaugh et al, 2006; Bäckhed, 2012). However, the microbial origins of obesity-associated metabolic inflammation and integration of host immune and bacterial sensing strategies are only beginning to be appreciated (Bäckhed, 2011; Burcelin et al, 2012; Holmes et al, 2012). We previously showed that gut microbial imbalance (i.e., dysbiosis) controls a state of metabolic endotoxemia during obesity and that bacterial factors from the gut, such as lipopolysaccharide (LPS), accumulated in the blood and contributed to inflammation and insulin intolerance through CD14/TLR4 pathogen-sensing systems (Cani et al, 2007, 2008; Poggi et al, 2007; Luche et al, 2013). Ablation of various pattern recognition receptors (PRRs) such as TLR4, CD14, PKR, and NLRP3 protect mice from diet-/obesity-induced inflammation and insulin resistance (Shi et al, 2006; Cani et al, 2007; Nakamura et al, 2010; Vandanmagsar et al, 2011). We previously showed that obese high-fat diet (HFD)-fed mice lacking both nucleotide oligomerization domain (NOD1) and NOD2 have reduced insulin resistance and inflammation (Schertzer et al, 2011). NOD1 and NOD2 are sensors of bacterial cell wall peptidoglycan (PGN) that elicit inflammation by augmenting cytokine, Paneth cell defensin (Stappenbeck et al, 2002), and stress kinase responses (Carneiro et al, 2008). We showed that PGN containing meso-DAP motifs (generally dominant in Gram-negative bacteria) caused profound insulin resistance through actions on NOD1 directly in metabolic cells, including adipocytes and hepatocytes (Schertzer et al, 2011). We also showed that NOD2 activation with the minimal bioactive PGN motif, muramyl dipeptide (MDP), more abundant in Gram-positive bacteria, elicited cell autonomous inflammation and impaired insulin action directly in muscle cells (Tamrakar et al, 2010) and could cause acute, transient, and peripheral insulin resistance in vivo (Schertzer et al, 2011). Hence, we originally hypothesized that lacking NOD2 detection of this type of PGN (i.e., MDP) would improve insulin sensitivity during obesity (Amar et al, 2011; Schertzer & Klip, 2011). We previously placed NOD2−/− mice on a diabetogenic diet (containing 70% fat and less than 1% carbohydrate), which does not cause overt obesity. We did not consider that NOD2 deletion could worsen insulin resistance and the dietary stress during this 70% HFD was not suitable to find (genetic) factors that potentially worsen insulin action or glucose regulation. However, this former work did reinforce that deletion of NOD1, but not NOD2, provided some protection from glucose intolerance under these severe dietary conditions (Amar et al, 2011). Metabolic differences due to deletion of NOD1 versus NOD2 would be consistent with the divergent results demonstrated by deletion of various NOD-like receptors in inflammasomes (Vandanmagsar et al, 2011; Henao-Mejia et al, 2012). Our current working model proposes that NOD1 deletion is protective (Amar et al, 2011), but to the best of our knowledge, no study has shown that defective PGN sensing by NOD2 may interact with a dietary stress to promote worse insulin resistance. This is a logical connection because defective NOD2 immunity has been associated with promoting other chronic pro-inflammatory pathologies, dysbiosis and human NOD2 variants have the highest risk association with Crohn's disease (Ogura et al, 2001). NOD2 immunity may also to contribute to gut microbial homeostasis, but the relevance to metabolic disease and insulin resistance has not yet been fully explored (Rehman et al, 2011). We demonstrate here that defective NOD2 sensing of PGN, either by NOD2 gene deletion or by mutations in PGN, promotes an increased bacterial invasion of metabolic tissues associated with inflammation and insulin resistance. Furthermore, the dysbiosis in mice continually bred with a NOD2-deletion plus the stress of an obesity-causing diet is an independent and transmissible factor that contributes to increased metabolic inflammation and insulin resistance. Results NOD2 deletion exacerbates HFD-induced insulin resistance First-generation NOD2+/+ and NOD2−/− littermates (bred from in-house NOD2-heterozygote parents) showed that deletion of NOD2 exacerbated insulin intolerance, independent of any difference in body mass, when the mice were fed a HFD for 16 weeks (Fig 1A and B). We used non-littermate mice for the remainder of the experiments. In order to specifically investigate diet-induced insulin resistance, we weight-matched WT and NOD2−/− mice after 16 weeks on the HFD. Overall, we did not find any metabolic differences in chow-fed wild-type (WT) and NOD2−/− mice, which had similar insulin tolerance and HOMA-IR (Fig 1C and D). However, HFD-fed NOD2−/− mice had exacerbated glucose tolerance (Supplementary Fig S1A–C) and higher HOMA-IR compared to weight-matched WT mice (Fig 1D). Hyperinsulinemic euglycemic clamps showed that weight-matched HFD-fed NOD2−/− mice had exacerbated whole body, hepatic insulin resistance determined by lower rates of glucose infusion (GINF), and lower insulin-induced suppression of hepatic glucose output (HGO), respectively (Fig 1E–G; Supplementary Fig S1D–F). We next generated mice that lacked NOD2 in the hematopoietic or non-hematopoietic compartments using lethal irradiation and bone marrow reconstitution. HFD-fed NOD2−/− mice that were reconstituted with WT bone marrow had worse glucose tolerance during a GTT and a higher HOMA-IR index when compared to WT mice that were reconstituted with either WT or NOD2-deficient bone marrow (Fig 1H and I). Therefore, NOD2 deletion in non-hematopoietic cells equated to worse glucose control during a HFD. Figure 1. NOD2 deletion in mice exacerbates diet-induced insulin resistance A, B. Body mass (A), blood glucose, and the cumulative area under the curve (AUC) (B) during insulin tolerance tests (ITT; 1.0 IU/kg i.p.) in NOD2+/+ (n = 8) and NOD2−/− (n = 10) littermate mice fed a HFD for 16 weeks, *P = 0.001. C. Blood glucose and the cumulative AUC during insulin tolerance tests (ITT; 0.5 IU/kg i.p.) in chow-fed WT (n = 6) and NOD2−/− (n = 6) mice. D. HOMA insulin resistance (IR) index in weight-matched chow- (n = 7) or HFD-fed (n = 10) WT and NOD2−/− mice, #P = 0.0001 (WT chow versus WT HFD) and *P = 0.0001 (WT HFD versus NOD2−/− HFD). E, F. Glucose infusion rate (GINF) (E) and glucose disposal rate (GDR) (F) during hyperinsulinemic euglycemic clamps in weight-matched WT (n = 4) and NOD2−/− (n = 3) mice fed a HFD for 16 weeks, *P = 0.02. G. Percentage of hepatic glucose output (HGO) suppression during hyperinsulinemic euglycemic clamps in weight-matched WT (n = 4) and NOD2−/− (n = 3) mice fed a HFD for 16 weeks, *P = 0.005. H. Blood glucose and cumulative AUC during glucose tolerance tests (GTT; 1.0 g/kg) in chow-fed (n = 3) or HFD-fed WT and NOD2−/− mice (n > 8 for all groups) after bone marrow transplantation, *P = 0.04 and ϕP = 0.01. I. HOMA-IR in chow-fed (n = 3) or HFD-fed WT and NOD2−/− mice (n > 8 for all groups) after bone marrow transplantation, ϕP = 0.003. Data information: *Significantly different from HFD-fed NOD2+/+ or WT mice or as indicated. #Significantly different from WT chow-fed mice. ϕSignificantly different from all other conditions. An unpaired t-test was used for comparisons between two conditions, whereas a 1-way ANOVA was used for comparisons between more than two conditions. Tukey's post-hoc test was used. Values are mean ± SEM. Download figure Download PowerPoint NOD2 deletion exacerbates diet-induced adipose tissue inflammation We found that a HFD increased NOD2 transcript levels in adipose tissue, muscle, and liver of WT mice and confirmed that NOD2−/− mice did not express NOD2 mRNA (Fig 2A). NOD1 transcript levels were not altered by genotype or diet in these tissues, and there were some diet-induced changes in other PRRs seen in the adipose and liver tissues (Supplementary Fig S1G–J). Within adipose tissue, the HFD increased NOD2 transcript levels in adipocytes (Supplementary Fig S2A). An abundance of non-adipocyte cells (dark stained by H&E) and macrophages (F4/80+) were detectable in the adipose tissue in HFD-fed NOD2−/− mice (Fig 2B; Supplementary Fig S2B). Higher transcript levels of adipose tissue Emr1 and CD11c were detected after the HFD, which were both significantly augmented in HFD-fed NOD2−/− mice compared to HFD-fed WT mice (Fig 2C). Transcript levels of IL-6 and TNF-α were elevated, and the ratio of iNOS/Arginase was elevated by more than 30-fold in adipose tissue of HFD-fed NOD2−/− mice (Fig 2C and D). Chow-fed WT and NOD2−/− mice were not different for these inflammatory markers (Fig 2C and D). Flow cytometry showed that NOD2−/− mice had higher macrophage and dendritic-like cells and higher CD3+ lymphocytes in the stromal vascular fraction (SVF) after 4 weeks on a very high-fat diet containing 70% Kcal from fat (Supplementary Fig S2C–F). Changes in inflammation were associated with defective adipose tissue function. For example, the ability of insulin to suppress lipolysis was blunted in HFD-fed NOD2−/− mice, since serum NEFA was higher during the clamp (Fig 2E). Adipose tissue also had defective insulin-induced signaling at the level of Akt phosphorylation (Fig 2F; Supplementary Fig S2K). Figure 2. Defects in NOD2 sensing of PGN promote gut bacterial translocation to adipose tissue and diet-induced adipose inflammation and dysfunction A. Transcript levels of NOD2 in various tissues of chow-fed (n = 5, all tissues in both genotypes) and 16 week HFD-fed (n = 6) WT and NOD2−/− mice, *P = 0.005, **P = 0.001, and ***P = 0.0004. B. H&E histology and IHC of the macrophage marker F4/80 in adipose tissue from HFD-fed WT and NOD2−/− mice (representative of n = 5 WT and n = 6 NOD2−/− mice). Scale bar equals 50 μm. C, D. Quantification of immune c" @default.
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• W2112708847 date "2015-02-09" @default.
• W2112708847 modified "2023-10-18" @default.
• W2112708847 title "Defective <scp>NOD</scp> 2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance" @default.
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• W2112708847 doi "https://doi.org/10.15252/emmm.201404169" @default.
• W2112708847 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4364944" @default.
• W2112708847 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25666722" @default.

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