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

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 - 2016/9/1

Y1 - 2016/9/1

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

SN - 0021-9738

VL - 126

SP - 3263

EP - 3278

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 9

ER -