FGF21 and the Physiological Regulation of Macronutrient Preference

Abstract The ability to respond to variations in nutritional status depends on regulatory systems that monitor nutrient intake and adaptively alter metabolism and feeding behavior during nutrient restriction. There is ample evidence that the restriction of water, sodium, or energy intake triggers adaptive responses that conserve existing nutrient stores and promote the ingestion of the missing nutrient, and that these homeostatic responses are mediated, at least in part, by nutritionally regulated hormones acting within the brain. This review highlights recent research that suggests that the metabolic hormone fibroblast growth factor 21 (FGF21) acts on the brain to homeostatically alter macronutrient preference. Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein, and exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein. In addition, while control mice adaptively shift macronutrient preference and increase protein intake in response to dietary protein restriction, mice that lack either FGF21 or FGF21 signaling in the brain fail to exhibit this homeostatic response. FGF21 therefore mediates a unique physiological niche, coordinating adaptive shifts in macronutrient preference that serve to maintain protein intake in the face of dietary protein restriction.

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Effects of dietary protein restriction on regional amino acid metabolism in insulin-dependent diabetes mellitus

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.1.e148 ◽

1996 ◽

Vol 270 (1) ◽

pp. E148-E157 ◽

Cited By ~ 2

Author(s):

I. G. Brodsky ◽

J. T. Devlin

Keyword(s):

Diabetes Mellitus ◽

Dietary Protein ◽

Protein Intake ◽

Insulin Dependent Diabetes Mellitus ◽

Protein Restriction ◽

Insulin Dependent Diabetes ◽

Whole Body ◽

Dependent Diabetes Mellitus ◽

Dietary Protein Restriction ◽

Insulin Dependent

We studied subjects with insulin-dependent diabetes mellitus (IDDM) and controls by administering primed continuous infusions of L-[1-13C,15N)]leucine and L-[2,3-13C2]alanine to measure whole body and forearm metabolism of these amino acids during ample protein intake and again after 4 wk of moderately restricted protein intake. Decreased rates of whole body protein degradation, leucine transamination, leucine oxidation, and increased forearm alanine release produced by dietary protein restriction occurred equivalently in IDDM subjects under short-term tightly managed glycemia and in controls. Dietary protein restriction did not affect whole body alanine appearance or forearm leucine appearance, disposal, or balance in IDDM subjects or controls. IDDM subjects differed from controls only in that normal forearm leucine balance was maintained at higher rates of leucine appearance and disposal. We conclude that IDDM subjects adapt normally to dietary protein restriction. Undernutrition during moderate protein deprivation in these patients likely occurs during episodes of poor glycemic control.

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Proximal tubule glutamine synthetase expression is necessary for the normal response to dietary protein restriction

AJP Renal Physiology ◽

10.1152/ajprenal.00048.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. F116-F125 ◽

Cited By ~ 9

Author(s):

Hyun-Wook Lee ◽

Gunars Osis ◽

Mary E. Handlogten ◽

Jill W. Verlander ◽

I. David Weiner

Keyword(s):

Glutamine Synthetase ◽

Proximal Tubule ◽

Dietary Protein ◽

Acid Production ◽

Protein Intake ◽

Ammonia Excretion ◽

Protein Restriction ◽

Protein Diet ◽

Acid Excretion ◽

Dietary Protein Restriction

Dietary protein restriction has multiple benefits in kidney disease. Because protein intake is a major determinant of endogenous acid production, it is important that net acid excretion changes in parallel during changes in dietary protein intake. Dietary protein restriction decreases endogenous acid production and decreases urinary ammonia excretion, a major component of net acid excretion. Glutamine synthetase (GS) catalyzes the reaction of [Formula: see text] and glutamate, which regenerates the essential amino acid glutamine and decreases net ammonia generation. Because renal proximal tubule GS expression increases during dietary protein restriction, this could contribute to the decreased ammonia excretion. The purpose of the current study was to determine the role of proximal tubule GS in the renal response to protein restriction. We generated mice with proximal tubule-specific GS deletion (PT-GS-KO) using Cre-loxP techniques. Cre-negative (Control) and PT-GS-KO mice in metabolic cages were provided 20% protein diet for 2 days and were then changed to low-protein (6%) diet for the next 7 days. Additional PT-GS-KO mice were maintained on 20% protein diet. Dietary protein restriction caused a rapid decrease in urinary ammonia excretion in both genotypes, but PT-GS-KO blunted this adaptive response significantly. This occurred despite no significant genotype-dependent differences in urinary pH or in serum electrolytes. There were no significant differences between Control and PT-GS-KO mice in expression of multiple other proteins involved in renal ammonia handling. We conclude that proximal tubule GS expression is necessary for the appropriate decrease in ammonia excretion during dietary protein restriction.

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FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

Scientific Reports ◽

10.1038/s41598-020-76593-2 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Kyle H. Flippo ◽

Sharon O. Jensen-Cody ◽

Kristin E. Claflin ◽

Matthew J. Potthoff

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Dietary Protein ◽

Body Weight Gain ◽

Protein Restriction ◽

Metabolic Effects ◽

Whole Body ◽

Fibroblast Growth Factor 21 ◽

Dietary Protein Restriction ◽

Glutamatergic Neurons

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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Effects of maternal dietary protein restriction on growth of the brain and body in the rat

Brain Research Bulletin ◽

10.1016/0361-9230(77)90009-0 ◽

1977 ◽

Vol 2 (2) ◽

pp. 131-135 ◽

Cited By ~ 26

Author(s):

W.B. Forbes ◽

C. Tracy ◽

O. Resnick ◽

P.J. Morgane

Keyword(s):

Dietary Protein ◽

Protein Restriction ◽

Dietary Protein Restriction ◽

The Brain

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Leucine Supplementation Does Not Restore Diminished Skeletal Muscle Satellite Cell Abundance and Myonuclear Accretion When Protein Intake Is Limiting in Neonatal Pigs

Journal of Nutrition ◽

10.1093/jn/nxz216 ◽

2019 ◽

Vol 150 (1) ◽

pp. 22-30

Author(s):

Marko Rudar ◽

Daniel A Columbus ◽

Julia Steinhoff-Wagner ◽

Agus Suryawan ◽

Hanh V Nguyen ◽

...

Keyword(s):

Skeletal Muscle ◽

G Protein ◽

Satellite Cell ◽

Dietary Protein ◽

Protein Intake ◽

Protein Restriction ◽

Dietary Protein Restriction ◽

Cell Abundance ◽

Neonatal Pigs ◽

Igf2 Expression

ABSTRACT Background Rapid growth of skeletal muscle in the neonate requires the coordination of protein deposition and myonuclear accretion. During this developmental stage, muscle protein synthesis is highly sensitive to amino acid supply, especially Leu, but we do not know if this is true for satellite cells, the source of muscle fiber myonuclei. Objective We examined whether dietary protein restriction reduces myonuclear accretion in the neonatal pig, and if any reduction in myonuclear accretion is mitigated by restoring Leu intake. Methods Neonatal pigs (1.53 ± 0.2 kg) were fitted with jugular vein and gastric catheters and fed 1 of 3 isoenergetic milk replacers every 4 h for 21 d: high protein [HP; 22.5 g protein/(kg/d); n= 8]; restricted protein [RP; 11.2 g protein/(kg/d); n= 10]; or restricted protein with Leu [RPL; 12.0 g protein/(kg/d); n= 10]. Pigs were administered 5-bromo-2’-deoxyuridine (BrdU; 15 mg/kg) intravenously every 12 h from days 6 to 8. Blood was sampled on days 6 and 21 to measure plasma Leu concentrations. On day 21, pigs were killed and the longissimus dorsi (LD) muscle was collected to measure cell morphometry, satellite cell abundance, myonuclear accretion, and insulin-like growth factor (IGF) system expression. Results Compared with HP pigs, postprandial plasma Leu concentration in RP pigs was 37% and 47% lower on days 6 and 21, respectively (P < 0.05); Leu supplementation in RPL pigs restored postprandial Leu to HP concentrations. Dietary protein restriction reduced LD myofiber cross-sectional area by 21%, satellite cell abundance by 35%, and BrdU+ myonuclear abundance by 25% (P < 0.05); Leu did not reverse these outcomes. Dietary protein restriction reduced LD muscle IGF2 expression by 60%, but not IGF1 or IGF1R expression (P < 0.05); Leu did not rescue IGF2 expression. Conclusions Satellite cell abundance and myonuclear accretion in neonatal pigs are compromised when dietary protein intake is restricted and are not restored with Leu supplementation.

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Influence of dietary protein restriction on immune competence. I. Effect on the capacity of cells from various lymphoid organs to induce graft-vs.-host reactions.

Journal of Experimental Medicine ◽

10.1084/jem.141.1.127 ◽

1975 ◽

Vol 141 (1) ◽

pp. 127-137 ◽

Cited By ~ 33

Author(s):

R G Bell ◽

L A Hazell

Keyword(s):

Dietary Protein ◽

Protein Restriction ◽

Lymphoid Organs ◽

Lymphoid Cells ◽

Host Responses ◽

Response Curves ◽

Dietary Protein Restriction ◽

The Face ◽

A Cell ◽

Lymph Node Cells

The effect of dietary protein restriction in mice on the capacity of their lymphoid cells to induce graft-vs.-host responses (GVHR) was studied. Mice were fed diets containing 4% or 20% protein ad libitum. The GVHR capacity of cells from all lymphoid organs of deprived mice was increased on a cell-for-cell basis over that of their normally fed counterparts. The slope of the dose-response curves did not change for spleen and mesenteric lymph node cells although their reactivity was increased by fourfold, and 50% respectively. The slope of the curves for thymus and Peyer's patches was changed indicating fundamental changes in the reactive cellular populations of these organs. Changes in GVH reactivity of cell populations from deprived mice were not mediated by increased corticosteroid production as adrenalectomy did not reduce their GVH responses. An explanation for the results was sought in a general decrease in production of short-lived cells with a rapid turnover such as most B cells. Long-lived T cells appear to persist and retain their reactivity for quite long periods in the face of nutritional insults.

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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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