title: Adipose- and muscle-derived Wnts trigger pancreatic β-cell adaptation to systemic insulin resistance.
abstract: Wnt signaling molecules are associated with obesity, hyperlipidemia, and type 2 diabetes (T2D). Here, we show that two Wnt proteins, WNT3a and WNT4, are specifically secreted by skeletal muscle and adipose tissue during the development of insulin resistance and play an important role in cross-talk between insulin-resistant tissues and pancreatic beta cells. The activation of Frizzled receptor and Wnt signaling in pancreatic islets via circulating WNT3a in blood resulted in higher insulin secretion and an increase in beta cell proliferation, thus leading to islet adaptation in a pre-diabetic state. Interestingly, in fully developed T2D, the expression profiles of Wnt3a and Wnt4 in adipose tissue and muscle cells and blood plasma levels of these proteins were opposite to the pre-diabetic state, thus favoring the downregulation of Wnt signaling in beta cells and resulting in dysfunctional pancreatic islets. These results demonstrate that alterations in the secretion profile of a canonical Wnt activator (WNT3a) and inhibitor (WNT4) from insulin-resistant tissues during the development of T2D are responsible for triggering progression from a pre-diabetic to a diabetic state. We also show here that WNT3a and WNT4 are potent myokines, and their expression and secretion are regulated in response to nutritional and metabolic changes.
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kozinski
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jazurek
authors.affiliation: Laboratory of Medical Molecular Biochemistry, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzyn
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Janikiewicz
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kolczynska
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gajda
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disorders, Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dobrzyn
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D017077:Culture Media, Conditioned; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology; D059305:Diet, High-Fat; D018450:Disease Progression; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060509:Wnt3A Protein / Q000378:metabolism*; D060528:Wnt4 Protein / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D060509:Wnt3A Protein; D060528:Wnt4 Protein