Overexpression of Adiponectin Receptor 1 Inhibits Brown and Beige Adipose Tissue Activity in Mice

Adult humans and mice possess significant classical brown adipose tissues (BAT) and, upon cold-induction, acquire brown-like adipocytes in certain depots of white adipose tissues (WAT), known as beige adipose tissues or WAT browning/beiging. Activating thermogenic classical BAT or WAT beiging to generate heat limits diet-induced obesity or type-2 diabetes in mice. Adiponectin is a beneficial adipokine resisting diabetes, and causing “healthy obese” by increasing WAT expansion to limit lipotoxicity in other metabolic tissues during high-fat feeding. However, the role of its receptors, especially adiponectin receptor 1 (AdipoR1), on cold-induced thermogenesis in vivo in BAT and in WAT beiging is still elusive. Here, we established a cold-induction procedure in transgenic mice over-expressing AdipoR1 and applied a live 3-D [18F] fluorodeoxyglucose-PET/CT (18F-FDG PET/CT) scanning to measure BAT activity by determining glucose uptake in cold-acclimated transgenic mice. Results showed that cold-acclimated mice over-expressing AdipoR1 had diminished cold-induced glucose uptake, enlarged adipocyte size in BAT and in browned WAT, and reduced surface BAT/body temperature in vivo. Furthermore, decreased gene expression, related to thermogenic Ucp1, BAT-specific markers, BAT-enriched mitochondrial markers, lipolysis and fatty acid oxidation, and increased expression of whitening genes in BAT or in browned subcutaneous inguinal WAT of AdipoR1 mice are congruent with results of PET/CT scanning and surface body temperature in vivo. Moreover, differentiated brown-like beige adipocytes isolated from pre-adipocytes in subcutaneous WAT of transgenic AdipoR1 mice also had similar effects of lowered expression of thermogenic Ucp1, BAT selective markers, and BAT mitochondrial markers. Therefore, this study combines in vitro and in vivo results with live 3-D scanning and reveals one of the many facets of the adiponectin receptors in regulating energy homeostasis, especially in the involvement of cold-induced thermogenesis.

The role of adiponectin and its receptor in patients with idiopathic membranous nephropathy complicated with hyperuricemia

Introduction/Objective. This study aimed to assess the changes of adiponectin (APN), IL-1?, adiponectin receptor 1 (Adipo R1), and NLRP3 expression of patients with idiopathic membranous nephropathy (IMN) complicated with hyperuricemia (HUA) and analyze the relationship between the APN pathway and the NLRP3 pathway. Methods. Forty-eight patients with IMN+HUA group, 49 patients with IMN group, 30 healthy controls, and 24 samples of healthy renal tissue were evaluated. APN and IL-1? of each group were detected by the ELISA method. AdipoR1 and NLRP3 in kidney tissue were detected by immunohistochemistry. The clinical data of each group were collected, and the relationship between APN, IL-1?, AdipoR1, NLRP3, and other indexes was analyzed. Results. (1) The concentration of UA, APN, IL-1?, and NLRP3 in the IMN+HUA group are significantly higher than those in the IMN group, but the AdipoR1 was lower. (2) With the severity of CKD stage, APN, IL-1?, and NLRP3 gradually increased in IMN+HUA group, but AdipoR1 gradually decreased. However, the above indicators did not change significantly in the IMN stages. Conclusion. The AdipoR1-AMPK and NLRP3-caspase-1-IL-1? signaling pathway may play an essential role in IMN+HUA patients. The intervention of these two pathways may make a great significance to the occurrence and progression on IMN+HUA patients.

Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 (ADIPOR1) as risk factors for HCM. Biochemical studies showed that ADIPOR1 variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal–regulated kinase pathways. A transgenic mouse model expressing an ADIPOR1 variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that ADIPOR1 variants can cause HCM and provide new insights into ADIPOR1 regulation.

Lung Regulatory T Cells Express Adiponectin Receptor 1: Modulation by Obesity and Airway Allergic Inflammation

Regulatory T cells (Tregs) decrease in the adipose tissue upon weight gain, contributing to persistent low-grade inflammation in obesity. We previously showed that adipose tissue Tregs express the adiponectin receptor 1 (AdipoR1); however, the expression in lung Tregs is still unknown. Here, we aimed to determine whether Helios+ and Helios− Treg subsets expressed AdipoR1 in the lungs of obese mice and whether different obesity grades affected the expression upon allergic lung inflammation. For diet-induced obesity (DIO), mice were fed a high-fat diet (HFD) for up to 15 weeks (overweight), 21 weeks (obesity), and 26 weeks (morbid obesity). Overweight and morbidly obese mice were sensitized and challenged with ovalbumin (OVA) to induce allergic lung inflammation. The AdipoR1 expression was reduced significantly in the lung Helios+ and Helios− Tregs of obese mice compared with lean mice. Airway allergic inflammation showed reduced AdipoR1 expression in lung Foxp3+ Tregs. Obesity significantly exacerbated the eosinophilic airway inflammation and reduced the number of Helios+ Tregs in lung and adipose tissue in the obesity-associated asthma model. Upon further weight gain, AdipoR1-expressing Tregs in the lungs of allergic mice were increased, whereas AdipoR1-expressing Tregs in adipose tissue were reduced. These data suggest that obesity-associated adipose tissue inflammation may exacerbate allergic inflammation by downregulating the AdipoR1+ Tregs in the lungs.

Cilostazol improves hyperglycemia-induced impaired vasculo-angiogenesis through stimulating adiponectin/adiponectin receptor 1/Sirtuin 1 signaling pathway

Background Cilostazol is an antiplatelet agent with vasodilating effect working through increasing intracellular concentration of cyclic adenosine monophosphate (AMP). We and others have previously found that cilostazol has a favorable effect on vasculo-angiogenesis. However, there is no study to evaluate the effect of cilostazol on adiponectin and its receptors. Purpose This study investigated the effects of cilostazol on adiponectin/adiponectin receptors and Sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) signaling pathway for preventing high glucose (HG)-induced impaired vasculo-angiogenesis in vitro and in vivo. Methods and results Human umbilical vein endothelial cells (HUVECs), seeded onto Transwell insert, and human aortic smooth muscle cells (HASMCs), seeded onto 6-well plate at lower level, were co-cultured in HG condition (25 mM). Adiponectin concentrations in the supernatant of 6-welll-plate and Transwell insert were significantly higher when HASMCs were treated with cilostazol in a dose-response manner but not significantly changed when only HUVECs were treated with cilostazol. HG downregulated protein expression of adiponectin receptor-1 (adipoR1), adipoR2, and Sirt1 and phosphorylation of AMPKα1, whereas cilostazol treatment restored expression of adipoR1 and Sirt1 proteins and upregulated phosphorylation of AMPKα1 in HUVECs treated with HG but not adipoR2. The stimulating effect of cilostazol on AMPKα1 or Sirt1 was attenuated with Sirt1 or AMPKα1 gene knockdown, respectively. By using gene knockdown of adiponectin receptors or AMPKα1, or treatment of the Sirt1 inhibitor, our data showed that cilostazol prevented apoptosis, and stimulated proliferation, chemotactic motility and capillary-like tube formation in HG-treated HUVECs through adipoR1, AMPK, and Sirt1 signaling pathway but not adipoR2. Fifteen-week-old male ICR hyperglycemic mice, induced by streptozosin injection and high cholesterol diet feeding, were treated intraperitoneally with cilostazol (10 mg/kg) 2 times per day since day 1 to day 7 after hindlimb ischemia. Recovery of blood flow ratio (ipsilateral/contralateral) in the ischemic hindlimb 14–21 days after surgery and circulating CD34+CD45dim cells were significantly attenuated by adipoR1 knockdown but not adipoR2. Capillary density in the ischemic muscles was significantly lower in both adipoR1- and adipoR2-knockdown mice. Expression of Sirt1 as well as phosphorylation of AMPKα1/acetyl-CoA carboxylase and Akt/endothelial nitric oxide synthase in ischemic muscles were significantly attenuated by gene knockdown of adipoR1 or adipoR2. Conclusions Our data suggest that cilostazol prevents high glucose-induced endothelial dysfunction in vascular endothelial cells as well as enhances vasculo-angiogenesis in hyperglycemic mice by upregulation of adiponectin/adipoR2 and its downstream signaling molecules, Sirt1/AMPK. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Ministry of Health and Welfare, Executive Yuan, Taiwan; The Ministry of Science and Technology, Executive Yuan, Taiwan

Adiponectin and adiponectin receptor 1 expression proteins levels are modified in breast cancer in postmenopausal women with obesity

AimTo analyse the expression of adiponectin (ADIPOQ), and its receptors ADIPOR1 and ADIPOR2, in breast cancer tissue of postmenopausal women with different body mass indexes (BMIs).Subjects and methodsOne hundred and fifty postmenopausal Mexican-Mestizo women with breast cancer were included. BMI was determined in each case. To carry out qualitative and semiquantitative assessments of protein expression by immunohistochemistry, the H-Score method was used, through ImageJ's IHC Profiler software. Statistical power of the study was >80% with a p<0.05.ResultsFifty women had a normal BMI, 50 presented overweight and 50 had obesity. The expression of ADIPOQ in breast cancer tissue of postmenopausal woman with normal BMI was higher in comparison to women with overweight or with obesity (p=0.002 and p<0.001, respectively). Furthermore, the expression of ADIPOR1 in breast cancer tissue of postmenopausal women with normal BMI was significantly lower when compared with women with overweight or with obesity (p=0.005 and p<0.001, respectively). Meanwhile, the expression of ADIPOR2 in breast cancer tissue, in the cytoplasm, was similar in all groups studied.ConclusionsWe found that women with overweight or obesity had a lower expression of ADIPOQ and a higher ADIPOR1 expression in breast cancer tissue, when compared with women with a normal BMI.