238-LB: Dietary Protein Restriction Induces Myocardial Dysfunction Despite Reducing Body Weight in Aged C57BL/6J Mice

Abstract Alterations in macronutrient intake can have profound effects on energy intake and whole-body metabolism. For example, reducing protein intake increases energy expenditure, increases insulin sensitivity and decreases body weight in rodents. Fibroblast growth factor 21 (FGF21) signaling in the brain is necessary for the metabolic effects of dietary protein restriction and has more recently been proposed to promote protein preference. However, the neuron populations through which FGF21 elicits these effects are unknown. Here, we demonstrate that deletion of β-klotho in glutamatergic, but not GABAergic, neurons abrogated the effects of dietary protein restriction on reducing body weight, but not on improving insulin sensitivity in both diet-induced obese and lean mice. Specifically, FGF21 signaling in glutamatergic neurons is necessary for protection against body weight gain and induction of UCP1 in adipose tissues associated with dietary protein restriction. However, β-klotho expression in glutamatergic neurons was dispensable for the effects of dietary protein restriction to increase insulin sensitivity. In addition, we report that FGF21 administration does not alter protein preference, but instead promotes the foraging of other macronutrients primarily by suppressing simple sugar consumption. This work provides important new insights into the neural substrates and mechanisms behind the endocrine control of metabolism during dietary protein dilution.

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NEURONAL FGF-21 SIGNALING: A SENSOR OF DIETARY PROTEIN

Innovation in Aging ◽

10.1093/geroni/igz038.2677 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S730-S730

Author(s):

Cristal Hill ◽

Christopher Morrison

Keyword(s):

Body Weight ◽

Energy Expenditure ◽

Glucose Homeostasis ◽

Dietary Protein ◽

Protein Restriction ◽

Fibroblast Growth Factor 21 ◽

Dietary Protein Restriction ◽

Reduced Body ◽

Low Protein ◽

The Central Nervous System

Abstract Our data demonstrates that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that this effect is largely mediated by the metabolic hormone fibroblast growth factor 21(FGF21). Considering that the central nervous system (CNS) is acknowledged as a major regulator of both energy and glucose homeostasis, we have extended our studies to identify the tissue site mediating these FGF21-dependent effects via dietary protein restriction. In this study, mice with dysfunctional FGF21-signaling in either the CNS or adipose tissue were fed a control or low protein (LP)-diet to assess changes in body weight and metabolic endpoints. Our data show that LP diet increased energy expenditure and reduced body weight in control littermates, but these effects were lost in mice bearing CNS-specific deletion of Klb. These data highlight a liver to brain FGF21-signal as the first known neuroendocrine mechanism to explain the coordinated metabolic changes induced by dietary protein restriction.

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Early dietary protein restriction slows disease progression and lengthens survival in mice with polycystic kidney disease.

Journal of the American Society of Nephrology ◽

10.1681/asn.v561355 ◽

1994 ◽

Vol 5 (6) ◽

pp. 1355-1360

Author(s):

K Tomobe ◽

D Philbrick ◽

H M Aukema ◽

W F Clark ◽

M R Ogborn ◽

...

Keyword(s):

Body Weight ◽

Kidney Disease ◽

Disease Progression ◽

Polycystic Kidney Disease ◽

Dietary Protein ◽

Protein Restriction ◽

Polycystic Kidney ◽

Kidney Weight ◽

Final Body Weight ◽

Dietary Protein Restriction

The objective of these studies was to examine the effects of early dietary protein restriction on disease progression and survival in the DBA/2FG-pcy (pcy) mouse model of polycystic kidney disease. Male pcy mice of 70 days of age were fed either a normal protein (NP, 25% casein) or a low-protein (LP, 6% casein) diet for 105 days. At the end of the dietary treatment, kidney weight, kidney weight relative to body weight and kidney water contents were almost 50% lower, and relative renal phospholipid and triglyceride contents were almost 50% higher, in mice fed the LP diet, indicating a marked reduction in the progression of cystic disease. Morphometric analyses also revealed a lower total and percent cyst area in kidneys derived from mice on the LP compared with the NP diet. There were no significant differences in final body weight, urine volume and osmolality, GFR, proteinuria, or plasma levels of protein and urea between these two groups. In a second study, it was found that all mice fed an NP diet from 70 days of age onward had died by 310 days of age, compared with a 42% survival rate in LP-fed mice at this age. Overall, the mean lifespan for pcy mice on the LP diet was 24% longer than that for those mice on the NP diet (310 +/- 20 versus 251 +/- 16 days; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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Severe Protein Restriction Activates Liver Protein Catabolism and ATF4-CHOP-TRB3 Pathway to Comprensate for Amino Acid Deficiency

Current Developments in Nutrition ◽

10.1093/cdn/nzaa049_040 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 647-647

Author(s):

Joanna Moro ◽

Juliane Calvez ◽

Catherine Chaumontet ◽

Patrick Even ◽

Julien Piedcoq ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Amino Acid ◽

Food Intake ◽

Dietary Protein ◽

Protein Restriction ◽

Liver Protein ◽

Protein Catabolism ◽

Dietary Protein Restriction ◽

Significant Difference

Abstract Objectives Severely low-protein diets (LP) induce behavioral and metabolic changes including a decrease in body weight, an increase in relative food intake (FI) and alterations in hepatic metabolism. During such protein restriction, changes in hepatic anabolic and catabolic protein pathways could transitory participate to compensate for amino acid (AA) deficiency. In the present study, liver expression of gene involved in proteosynthesis and proteolysis pathways, were related to FI, blood AA levels and body composition in rats fed LP diet. Methods Growing rats were fed for three weeks different diets containing 3-5-8-12-15 or 20% energy of milk protein. Body weight and FI were measured daily. At the end of the experiment, tissues and biological fluids were removed for gene expression measurement and blood AA UPLC analysis. Statistical analysis was done by 1- or 2-factor ANOVA, when data were repeated. Results Despite an increase in relative food intake under P3 and P5% diets, P3, P5 and P8% diets resulted in significant growth retardation compared to other groups. Lean mass was significantly decreased in rats under P3, P5 and P8% compared to P12, P15 and P20% diets, while there was no difference in fat mass between all groups. P3, P5 and P8% diets induced a decrease in essential amino acid concentrations in portal vein, whereas there was no significant difference between groups in veina cava. Severely protein restricted P3% and P5% diets induced an increase in hepatic gene expression involved in proteolysis as calpain 2 and ubiquitin, and an activation of ATF4-CHOP-TRB3 pathway. Conclusions These results suggested that under severe protein restriction, hepatic protein catabolism became a source of plasma amino acid that could partially compensate for the AA not provided by the diet. These observations confirm that liver plays a major role in the adaptation of the body to dietary protein restriction and highlight that severe dietary protein restriction induced liver protein catabolism by inducing an activation of ATF4-CHOP-TRB3 pathway in order to provide amino acids to body tissues. Funding Sources ABIES, AlimH-INRAE.

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Role of FGF21 and GCN2 in mediating the metabolic response to dietary protein restriction

Diabetologie und Stoffwechsel ◽

10.1055/s-0036-1580771 ◽

2016 ◽

Vol 11 (S 01) ◽

Author(s):

T Laeger ◽

DC Albarado ◽

L Trosclair ◽

J Hedgepeth ◽

CD Morrison

Keyword(s):

Dietary Protein ◽

Metabolic Response ◽

Protein Restriction ◽

Dietary Protein Restriction

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Neuronal FGF-21 Signaling–A Sensor of Dietary Protein Restriction

Diabetes ◽

10.2337/db18-261-lb ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 261-LB

Author(s):

CRISTAL M. HILL ◽

MADELEINE V. DEHNER ◽

DAVID MCDOUGAL ◽

HANS-RUDOLF BERTHOUD ◽

HEIKE MUENZBERG ◽

...

Keyword(s):

Dietary Protein ◽

Protein Restriction ◽

Dietary Protein Restriction

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The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein

Nutrients ◽

10.3390/nu13082609 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2609

Author(s):

Han Fang ◽

Kirsten P. Stone ◽

Sujoy Ghosh ◽

Laura A. Forney ◽

Thomas W. Gettys

Keyword(s):

Amino Acids ◽

Dietary Protein ◽

Target Genes ◽

Protein Restriction ◽

Metabolic Phenotype ◽

Sulfur Amino Acids ◽

Transcriptional Responses ◽

Similar Reduction ◽

Dietary Protein Restriction ◽

Methionine Restriction

Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.

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