A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution. / Maida, Adriano; Zota, Annika; Sjøberg, Kim Anker; Schumacher, Jonas; Sijmonsma, Tjeerd P; Pfenninger, Anja; Christensen, Marie Møller; Gantert, Thomas; Fuhrmeister, Jessica; Rothermel, Ulrike; Schmoll, Dieter; Heikenwälder, Mathias; Iovanna, Juan L; Stemmer, Kerstin; Kiens, Bente; Herzig, Stephan; Rose, Adam John.
In: Journal of Clinical Investigation, Vol. 126, No. 9, 2016, p. 3263-3278.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
AU - Maida, Adriano
AU - Zota, Annika
AU - Sjøberg, Kim Anker
AU - Schumacher, Jonas
AU - Sijmonsma, Tjeerd P
AU - Pfenninger, Anja
AU - Christensen, Marie Møller
AU - Gantert, Thomas
AU - Fuhrmeister, Jessica
AU - Rothermel, Ulrike
AU - Schmoll, Dieter
AU - Heikenwälder, Mathias
AU - Iovanna, Juan L
AU - Stemmer, Kerstin
AU - Kiens, Bente
AU - Herzig, Stephan
AU - Rose, Adam John
N1 - CURIS 2016 NEXS 238
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1172/JCI85946
DO - 10.1172/JCI85946
M3 - Journal article
C2 - 27548521
VL - 126
SP - 3263
EP - 3278
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -
ID: 164817186