ESPE2022 Free Communications Fat, Metabolism and Obesity (6 abstracts)
Inhibition of Neuritin 1 induces browning in human white adipocytes and protects from obesity in vivo
Daniel Tews 1 , Julian Roos 2 , Gordon Winter 3 , Ambros Beer 3 , Volker Rasche 4 , Elly Nedivi 5 , Klaus-Michael Debatin 2 , Martin Wabitsch 1 & Pamela Fischer-Posovszky 2
1Division of Pediatric Endocrinology and Diabetes, Ulm University Medical Center, Ulm, Germany; 2Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany; 3Clinic for Nuclear Medicine, Ulm University Medical Center, Ulm, Germany; 4Department of Internal Medicine II, Ulm, Germany; 5Department of Brain and cognitive Sciences, Massachusetts Institute of Technology, Cambridge, USA
Recently, we identified Neuritin 1 (NRN1) as preferentially expressed in human white compared to brown adipocyte progenitor cells. In mice, Nrn1 deficiency leads to a reduction in body weight, indicating that it might regulate body weight. In this study, we aim to address the function of NRN1 regarding adipocyte metabolism in vitro and in vivo. We used human SGBS preadipocytes as an in vitro model system. NRN1-deficient cells were generated using lentiviral miRNA constructs. In vivo effects were studied in Nrn1-deficient mice. In human preadipocytes, NRN1 deficiency did not interfere with adipogenic differentiation, but resulted in an increase of basal glucose uptake by 60%, accompanied by increased GLUT1 mRNA levels. Further, NRN1 knockdown significantly induced mRNA and protein levels of UCP1, and resulted in increased basal and cAMP-mediated uncoupling, suggesting that NRN1 might be involved in the regulation of adipocyte browning. In Nrn1 deficient mice, lower body weight was accompanied by reduced relative inguinal and gonadal fat pad weights (both -28% vs wt). Although we could not detect alterations in browning markers in white adipose tissue (WAT) between wildtype and Nrn1-deficient mice, we found that treatment with the ß3-adrenergic agonist CL316243 lead to a significant increase of glucose uptake in WAT of Nrn1-deficient mice by 2.2-fold (iWAT) and 4.3-fold (gWAT). To further investigate if Nrn1 has an impact on body weight regulation, mice were challenged with a high-fat diet for 12 weeks. Of note, Nrn1-deficient mice gained 30% less weight compared to wt controls, accompanied by reduced white fat pad mass. Additionally, Nrn1-deficient mice were protected from liver steatosis. Our data suggest that inhibition of neuritin 1 affects fat cell metabolism. We are currently investigating species differences between human and mouse.
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