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1.
Artigo em Inglês | MEDLINE | ID: mdl-31479202

RESUMO

The discovery that functional brown adipose tissue (BAT) in adult humans is inversely related to body fat mass and may reflect metabolic health has stimulated adipose tissue research to explore activation of BAT as a potential target for antiobesity treatments. In addition to the capacity of BAT to increase energy expenditure and glucose and lipid uptake, BAT secretes factors that may contribute to the regulation of whole-body metabolism. Among signals released from BAT, neuregulin 4 (NRG4) has been recently identified as an endocrine factor that may link the activation of BAT to protection against diet-induced obesity, insulin resistance, and hepatic steatosis. NRG4 was shown to directly reduce lipogenesis in hepatocytes, and it could indirectly activate BAT via sympathetic neurons or via inducing brown adipocyte-like signatures in white adipocytes in a paracrine manner. However, the potential relevance of NRG4 as a diagnostic tool or target for the treatment of obesity-related diseases remains to be explored.

5.
Mol Metab ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31427184

RESUMO

OBJECTIVE: Obesity and type-2 diabetes (T2D) are metabolic diseases that represent a critical health problem worldwide. Metabolic disease is differentially associated with fat distribution, while visceral white adipose tissue (VAT) is particularly prone to obesity-associated inflammation. Next to their canonical function of immune suppression, regulatory T cells (Tregs) are key in controlling adipose tissue homeostasis. Towards understanding the molecular underpinnings of metabolic disease, we focus on how environmental-metabolic stimuli impinge on the functional interplay between Tregs and adipose tissue. Here, cold exposure or beta3-adrenergic signaling are a promising tool to increase energy expenditure by activating brown adipose tissue, as well as by reducing local inflammation within fat depots by supporting immunosuppressive Tregs. However, in humans, the underlying mechanisms that enable the environmental-immune crosstalk in the periphery and in the respective tissue remain currently unknown. METHODS: We used combinatorial approaches of next generation humanized mouse models and in vitro and in vivo experiments together with beta3-adrenergic stimulation to dissect the underlying mechanisms of human Treg induction exposed to environmental stimuli such as cold. To test the translational relevance of our findings, we analyzed samples from the FREECE study in which human subjects were exposed to individualized cooling protocols. Samples were analyzed ex vivo and after in vitro Treg induction using qRT-PCR, immunofluorescence, as well as with multicolor flow cytometry and cell sorting. RESULTS: In vivo application of the beta3-adrenergic receptor agonist mirabegron in humanized mice induced thermogenesis and improved the Treg induction capacity of naïve T cells isolated from these animals. Using samples from the human FREECE study, we demonstrate that a short-term cold stimulus supports human Treg induction in vitro and in vivo. Mechanistically, we identify BORCS6 encoding the Ragulator-interacting protein C17orf59 to be significantly induced in human CD4+ T cells upon short-term cold exposure. Strong mTOR signaling is known to limit successful Treg induction and thus likely by interfering with mTOR activation at lysosomal surfaces, C17orf59 improves the Treg induction capacity of human naïve T cells upon cold exposure. CONCLUSIONS: These novel insights into the molecular underpinnings of human Treg induction suggest an important role of Tregs in linking environmental stimuli with adipose tissue function and metabolic diseases. Moreover, these discoveries shed new light on potential approaches towards tailored anti-inflammatory concepts that support human adipose tissue homeostasis by enabling Tregs.

6.
Front Immunol ; 10: 1874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440251

RESUMO

Circulating monocytes can be divided into classical (CM), intermediate (IM), and non-classical monocytes (NCM), and the classical monocytes also contain CD56+ monocytes and monocytic myeloid-derived suppressor cells (M-MDSC). The aim of the study was to evaluate the occurrence of the monocyte subpopulations in human obesity. Twenty-seven normal, 23 overweight, and 60 obese individuals (including 17 obese individuals with normal glucose tolerance and 27 with type 2 diabetes) were included into this study. Peripheral blood mononuclear cells were isolated from human blood, and surface markers to identify monocyte subpopulations were analyzed by flow cytometry. Obese individuals had higher numbers of total monocytes, CM, IM, CD56+ monocytes, and M-MDSCs. The number of CM, IM, CD56+ monocytes, and M-MDSCs, correlated positively with body mass index, body fat, waist circumference, triglycerides, C-reactive protein, and HbA1c, and negatively with high-density lipoprotein cholesterol. Individuals with obesity and type 2 diabetes had higher numbers of IM, NCM, and M-MDSCs, whereas those with obesity and impaired glucose tolerance had higher numbers of CD56+ monocytes. In summary, the comprehensive analysis of blood monocytes in human obesity revealed a shift of the monocyte compartment toward pro-inflammatory monocytes which might contribute to the development of low-grade inflammation in obesity, and immune-suppressive monocytes which might contribute to the development of cancer in obesity.

8.
Cell Metab ; 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31353262

RESUMO

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and ß3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.

9.
EMBO Mol Med ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171651

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal-regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High-fat diet-fed and aged chow-fed liver-specific ASK1-knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild-type mice. In line, liver-specific ASK1 overexpression protected mice from the development of high-fat diet-induced hepatic steatosis and carbon tetrachloride-induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31225870

RESUMO

CONTEXT: In obese individuals, adipocyte endocrine function is affected by altered autophagy. Genetic variants in autophagy-related gene 7 (ATG7) correlated with serum chemerin (RARRES2) concentrations. OBJECTIVES: To investigate a functional interplay between chemerin and ATG7, how it may relate to autophagy-mediated adipocyte dysfunction in obesity, and the relevance of genetic ATG7-variants in chemerin physiology. DESIGN: Adipose ATG7-mRNA expression and adiposity measures were available in two human study cohorts. The effect of a high-calorie diet on adipose Rarres2 and Atg7-expression was investigated in mice. In 3T3L1-adipocytes, the effect of Atg7-knockdown on chemerin expression and secretion was studied. The influence of single nucleotide polymorphisms on ATG7-transcription and chemerin physiology were investigated using a luciferase assay. SETTING: Mouse model, clinical trials, in vitro studies. PARTICIPANTS: Native American (n=83) and Caucasian (n=100) cohort. MAIN OUTCOME MEASURE: Adipocyte chemerin expression and secretion. RESULTS: In mice fed a high-calorie diet, adipose Atg7-mRNA expression did not parallel an increase in Rarres2-mRNA expression. ATG7-mRNA expression in human subcutaneous adipose tissue correlated with BMI, fat mass (r > 0.27, P < 0.01), and adipocyte cell size (r > 0.42, P < 0.02). Atg7-knockdown in 3T3L1-adipocytes decreased chemerin secretion by 22% (P < 0.04). Rs2606729 in ATG7 was predicted to alter ATG7-transcription and induced higher luciferase activity in vitro (P < 0.0001). CONCLUSIONS: Human adipose ATG7-mRNA expression relates to measures of adiposity. Atg7-knockdown reduces chemerin secretion from adipocytes in vitro supportive of a functional interplay between ATG7 and chemerin in autophagy-mediated adipocyte dysfunction.

12.
Eur J Endocrinol ; 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153139

RESUMO

OBJECTIVE: Neuregulin 4 (Nrg4) has recently been introduced as a novel brown adipose tissue (BAT)-secreted adipokine with beneficial metabolic effects in mice. However, regulation of Nrg4 in end-stage kidney disease (ESKD) and type 2 diabetes mellitus (T2DM) has not been elucidated, so far. DESIGN/METHODS: Serum Nrg4 levels were quantified by ELISA in 60 subjects with ESKD on chronic hemodialysis as compared to 60 subjects with an estimated glomerular filtration rate >50 ml/min/1.73m² in a cross-sectional cohort. Within both groups, about half of the patients had a T2DM. Furthermore, mNrg4 mRNA expression was determined in two mouse models of diabetic kidney disease (DKD) as compared to two different groups of non-diabetic control mice. Moreover, mNrg4 mRNA expression was investigated in murine brown and white adipocytes, as well as hepatocytes, after treatment with the uremic toxin indoxyl sulfate. RESULTS: Median serum Nrg4 was significantly lower in patients with ESKD compared to controls and the adipokine was independently associated with a beneficial renal, glucose, and lipid profile. In mice with DKD, mNrg4 mRNA expression was decreased in all adipose tissue depots compared to control mice. The uremic toxin indoxyl sulfate did not significantly alter mNrg4 mRNA expression in adipocytes and hepatocytes, in vitro. CONCLUSIONS: Circulating Nrg4 is independently associated with a preserved renal function and mNrg4 mRNA expression is reduced in adipose tissue depots of mice with DKD. The BAT-secreted adipokine is further associated with a beneficial glucose and lipid profile supporting Nrg4 as potential treatment target in metabolic and renal disease states.

13.
EBioMedicine ; 44: 476-488, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153815

RESUMO

BACKGROUND: In brain, CREB-regulated transcription co-activator 1 (CRTC1) is involved in metabolic dysregulation. In humans a SNP in CRTC1 was associated to body fat percentage and two SNPs affected RNA Pol II binding and chromatin structure, implying epigenetic regulation of CRTC1. We sought to understand the relevance of CRTC1 SNPs, DNA methylation and expression in human eating behaviour and its relationship to clinical variables of obesity in blood and adipose tissue. METHODS: 13 CRTC1 SNPs were included to analyze eating behaviour. For rs7256986, follow up association analyses were applied on DNA methylation, CRTC1 expression and clinical parameters. Linear regression was used throughout the study adjusted for age, sex and BMI. Besides data extraction from previous work, rs7256986 was de-novo genotyped and DNA methylation was evaluated by using pyrosequencing. FINDINGS: We found several SNPs in the CRTC1 locus nominally associated with human eating behaviour or 2hr postprandial insulin levels and observed a correlation with alcohol and coffee intake (all P < 0.05). G-allele carriers of rs7256986 showed slightly increased hip circumference. We showed that rs7256986 represents a methylation quantitative trait locus (meQTL) in whole blood and adipose tissue. The presence of the SNP and/or DNA methylation correlated with CRTC1 gene expression which in turn, related to BMI and fat distribution. INTERPRETATION: Our data support the known role of CRCT1 regulating energy metabolism in brain. Here, we highlight relevance of CRTC1 regulation in blood and adipose tissue. FUND: IFB AdiposityDiseases (BMBF); n609020-Scientia Fellows; Helse-SørØst; DFG: CRC 1052/1 and/2; Kompetenznetz Adipositas, German Diabetes Association.

14.
Am J Hum Genet ; 105(1): 15-28, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178129

RESUMO

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

15.
FASEB J ; 33(9): 9974-9989, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31173506

RESUMO

Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20-like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating ß-oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl-coenzyme A carboxylase protein abundance were reduced in MST3-deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.-Cansby, E., Kulkarni, N. M., Magnusson, E., Kurhe, Y., Amrutkar, M., Nerstedt, A., Ståhlman, M., Sihlbom, C., Marschall, H.-U., Borén, J., Blüher, M., Mahlapuu, M. Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans.

16.
Diabetes Care ; 42(7): 1162-1169, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31076421

RESUMO

OBJECTIVE: To compare the postprandial and overnight glycemic response using a novel green aquatic plant thought to provide a dietary source for high-quality protein, with an iso-carbohydrate/protein/caloric dairy shake. RESEARCH DESIGN AND METHODS: This is a randomized controlled crossover trial among 20 abdominally obese participants (age 51.4 years; fasting plasma glucose 110.9 mg/dL), who were allocated to replace dinner with either, first, a green shake containing Wolffia globosa duckweed (Mankai: specific-strain) or an iso-carbohydrate/protein/calorie yogurt shake. A 2-week flash glucose-monitoring system was used to assess postmeal glucose dynamics (6 net administration days; 97 observation days in total). We further obtained from each participant dietary/daily activity/satiety scale/sleep logs. Participants were recruited from the green-Mediterranean diet arm of the 18-month Dietary Intervention Randomized Controlled Trial-Polyphenols Unprocessed (DIRECT-PLUS) study. RESULTS: Wolffia globosa Mankai elicited a lower postprandial glucose peak compared with yogurt (∆peak = 13.4 ± 9.2 vs. 19.3 ± 15.1 mg/dL; P = 0.044), which occurred later (77.5 ± 29.2 vs. 59.2 ± 28.4 min; P = 0.037) and returned faster to baseline glucose levels (135.8 ± 53.1 vs. 197.5 ± 70.2 min; P = 0.012). The mean post-net incremental area under the curve (netAUC) was lower with Wolffia globosa up to 60 and 180 min (netAUC 60 min: 185.1 ± 340.1 vs. 441.4 ± 336.5 mg/dL/min, P = 0.005; netAUC 180 min: 707.9 ± 1,428.5 vs. 1,576.6 ± 1,810.1 mg/dL/min, P = 0.037). A Wolffia globosa-based shake replacing dinner resulted in lower next-morning fasting glucose levels (83.2 ± 0.8 vs. 86.6 ± 13 mg/dL; P = 0.041). Overall, postprandial glucose levels from the shake administration until the next morning were lower in the Wolffia globosa Mankai green shake compared with the yogurt shake (P < 0.001). Overnight sleep duration was similar (378.2 ± 22.4 vs. 375.9 ± 28.4 min; P = 0.72), and satiety rank was slightly higher for the Wolffia globosa shake compared with the yogurt shake (7.5 vs. 6.5; P = 0.035). CONCLUSIONS: Wolffia globosa Mankai duckweed may serve as an emerging alternative plant protein source with potential beneficial postprandial glycemic effects.

17.
J Hepatol ; 71(2): 379-388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075323

RESUMO

BACKGROUND & AIM: It is unclear if a reduction in hepatic fat content (HFC) is a major mediator of the cardiometabolic benefit of lifestyle intervention, and whether it has prognostic significance beyond the loss of visceral adipose tissue (VAT). In the present sub-study, we hypothesized that HFC loss in response to dietary interventions induces specific beneficial effects independently of VAT changes. METHODS: In an 18-month weight-loss trial, 278 participants with abdominal obesity/dyslipidemia were randomized to low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC + 28 g walnuts/day) diets with/without moderate physical activity. HFC and abdominal fat-depots were measured using magnetic resonance imaging at baseline, after 6 (sub-study, n = 158) and 18 months. RESULTS: Of 278 participants (mean HFC 10.2% [range: 0.01%-50.4%]), the retention rate was 86.3%. The %HFC substantially decreased after 6 months (-6.6% absolute units [-41% relatively]) and 18 months (-4.0% absolute units [-29% relatively]; p <0.001 vs. baseline). Reductions of HFC were associated with decreases in VAT beyond weight loss. After controlling for VAT loss, decreased %HFC remained independently associated with reductions in serum gamma glutamyltransferase and alanine aminotransferase, circulating chemerin, and glycated hemoglobin (p <0.05). While the reduction in HFC was similar between physical activity groups, MED/LC induced a greater %HFC decrease (p = 0.036) and greater improvements in cardiometabolic risk parameters (p <0.05) than the LF diet, even after controlling for VAT changes. Yet, the greater improvements in cardiometabolic risk parameters induced by MED/LC were all markedly attenuated when controlling for HFC changes. CONCLUSIONS: %HFC is substantially reduced by diet-induced moderate weight loss and is more effectively reduced by the MED/LC diet than the LF diet, independently of VAT changes. The beneficial effects of the MED/LC diet on specific cardiometabolic parameters appear to be mediated more by decreases in %HFC than VAT loss. LAY SUMMARY: High hepatic fat content is associated with metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease. In the CENTRAL 18-month intervention trial, a Mediterranean/low-carbohydrate diet induced a greater decrease in hepatic fat content than a low-fat diet, conferring beneficial health effects that were beyond the favorable effects of visceral fat loss. ClinicalTrials.gov Identifier: NCT01530724.

19.
Immunity ; 50(5): 1232-1248.e14, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31027998

RESUMO

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.

20.
Neuroscience ; 406: 496-509, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30867132

RESUMO

Peripheral diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Previous studies showed an association between dietary iron load and inflammation in the development of PDN in a rat model of type 1 diabetes (T1D). Here we investigated the role of iron and neural inflammation in development of PDN in a animal model of obesity and type 2 diabetes (T2D). 3-month-old db/db mice were fed with a high, standard or low iron diet for 4 months. High iron chow lead to a significant increase in motor nerve conduction velocities compared to mice on standard and low iron chow. Direct beneficiary effects on lowering blood glucose and HbA1c concentrations were shown in the high iron treated diabetic mice. Numbers of pro-inflammatory M1 macrophages were reduced in nerve sections, and anti-inflammatory M2 macrophages were increased in db/db mice on high iron diet compared to other groups. These results confirm and extend our previous findings in STZ-diabetic rats by showing that dietary non-hem iron supplementation may partly prevent the development of PDN in opposition to iron restriction. The identification of these dietary iron effects on the metabolic and inflammatory mechanisms of PDN supports a role of dietary iron and leads us to suggest testing for iron levels in human diabetic patients.

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