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Maida, A. ; Zota, A. ; Sjøberg, K.A.* ; Schumacher, J.* ; Sijmonsma, T.P.* ; Pfenninger, A.* ; Christensen, M.M.* ; Gantert, T.* ; Fuhrmeister, J.* ; Rothermel, U.* ; Schmoll, D.* ; Heikenwälder, M.* ; Iovanna, J.L.* ; Stemmer, K. ; Kiens, B.* ; Herzig, S. ; Rose, A.J.*

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution.

J. Clin. Invest. 126, 3263-3278 (2016)
Publ. Version/Full Text Supplement DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Dietary protein intake is linked to an increased incidence of type 2 diabetes (T2D). Although dietary protein dilution (DPD) can slow the progression of some aging-related disorders, whether this strategy affects the development and risk for obesity-associated metabolic disease such as T2D is unclear. Here, we determined that DPD in mice and humans increases serum markers of metabolic health. In lean mice, DPD promoted metabolic inefficiency by increasing carbohydrate and fat oxidation. In nutritional and polygenic murine models of obesity, DPD prevented and curtailed the development of impaired glucose homeostasis independently of obesity and food intake. DPD-mediated metabolic inefficiency and improvement of glucose homeostasis were independent of uncoupling protein 1 (UCP1), but required expression of liver-derived fibroblast growth factor 21 (FGF21) in both lean and obese mice. FGF21 expression and secretion as well as the associated metabolic remodeling induced by DPD also required induction of liver-integrated stress response-driven nuclear protein 1 (NUPR1). Insufficiency of select nonessential amino acids (NEAAs) was necessary and adequate for NUPR1 and subsequent FGF21 induction and secretion in hepatocytes in vitro and in vivo. Taken together, these data indicate that DPD promotes improved glucose homeostasis through an NEAA insufficiency-induced liver NUPR1/FGF21 axis.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Amino-acid Deprivation; Growth-factor 21; Brown Adipose-tissue; Energy-balance; Methionine Restriction; Insulin-resistance; Mice Lacking; In-vivo; Nonshivering Thermogenesis; Transcriptional Activation
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 126, Issue: 9, Pages: 3263-3278 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place Ann Arbor
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Diabetes and Obesity (IDO)