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

2020 ◽  
Vol 10 (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.

scholarly journals NEURONAL FGF-21 SIGNALING: A SENSOR OF DIETARY PROTEIN

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.

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

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 238-LB
Author(s):  
CHRISTOPHER L. AXELROD ◽  
WAGNER S. DANTAS ◽  
GANGARAO DAVULURI ◽  
WILLIAM T. KING ◽  
CRISTAL M. HILL ◽  
...  
Keyword(s):  
Body Weight ◽  
Dietary Protein ◽  
Myocardial Dysfunction ◽  
Protein Restriction ◽  
Dietary Protein Restriction

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

1996 ◽  
Vol 270 (1) ◽  
pp. E148-E157 ◽  
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.

scholarly journals Short-term Ketogenic Diet Induces a Molecular Response that is Distinct from Dietary Protein Restriction

2021 ◽  
Author(s):  
Krystle Kalafut ◽  
Sarah J Mitchell ◽  
Michael R MacArthur ◽  
James R Mitchell
Keyword(s):  
Weight Loss ◽  
Insulin Sensitivity ◽  
Protein Content ◽  
Ketogenic Diet ◽  
Dietary Protein ◽  
Control Diet ◽  
Protein Restriction ◽  
Short Term ◽  
Dietary Protein Restriction ◽  
Ketogenic Diets

There is increasing interest in utilizing short-term dietary interventions in the contexts of cancer, surgical stress and metabolic disease. These short-term diets may be more feasible than extended interventions and may be designed to complement existing therapies. In particular, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used to treat epilepsy, has gained popularity as a potential strategy for weight loss and improved metabolic health. In mice, long-term KD improves insulin sensitivity and extends lifespan and healthspan. Dietary protein restriction (PR) causes increased energy expenditure, weight loss and improved glucose homeostasis. Since KD is inherently a low-protein diet (10% of calories from protein vs. 20% in control diet), here we evaluated the potential for mechanistic overlap between PR and KD via activation of a PR response. Mice were fed control, protein-free (PF), or one of four ketogenic diets with varying protein content for 8 days. PF and KD diets both decreased body weight, fat mass, and liver weights, and reduced fasting glucose and insulin levels, compared to mice fed the control diet. However, PF and KD differed with respect to insulin tolerance and hepatic insulin sensitivity, which were increased in PF-fed mice and impaired in KD-fed mice relative to controls. Furthermore, contrary to the PF-fed mice, mice fed ketogenic diets containing at least 5% protein did not increase hepatic Fgf21 or brown adipose Ucp1 expression. Interestingly, mice fed KD lacking protein demonstrated greater elevations in hepatic Fgf21 than mice fed a low-fat PF diet. To further elucidate potential mechanistic differences between PF and KD diets and the interplay between dietary protein and carbohydrate restriction, we conducted RNA-seq analysis on livers from mice fed each of the six diets and identified distinct gene sets which respond to dietary protein content, dietary fat content, and ketogenesis. We conclude that KD with 10% of energy from protein does not induce a protein restriction response, and that the overlapping metabolic benefits of KD and PF diets occur via distinct underlying mechanisms.

Reduced Albuminuria and Improved Insulin Sensitivity After Dietary Protein Restriction in IDDM Patients

Diabetes Care ◽  
1989 ◽  
Vol 12 (5) ◽  
pp. 369-370 ◽  
Author(s):  
H. Gin ◽  
M. Aparicio ◽  
L. Potaux ◽  
J.-L. Bouchet ◽  
J. Aubertin
Keyword(s):  
Insulin Sensitivity ◽  
Dietary Protein ◽  
Protein Restriction ◽  
Dietary Protein Restriction

scholarly journals FGF21 and the Physiological Regulation of Macronutrient Preference

Endocrinology ◽  
2020 ◽  
Vol 161 (3) ◽  
Author(s):  
Cristal M Hill ◽  
Emily Qualls-Creekmore ◽  
Hans-Rudolf Berthoud ◽  
Paul Soto ◽  
Sangho Yu ◽  
...  
Keyword(s):  
Dietary Protein ◽  
Protein Intake ◽  
Protein Restriction ◽  
Fibroblast Growth Factor 21 ◽  
Adaptive Responses ◽  
Ample Evidence ◽  
Dietary Protein Restriction ◽  
The Face ◽  
Increase Protein Intake ◽  
The Brain

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.

Effect of protein restriction on sulfur amino acid catabolism in insulin-dependent diabetes mellitus

2003 ◽  
Vol 284 (2) ◽  
pp. E382-E389 ◽  
Author(s):  
Mazen J. Hamadeh ◽  
L. John Hoffer
Keyword(s):  
Dietary Protein ◽  
Normal Subjects ◽  
Insulin Dependent Diabetes Mellitus ◽  
Protein Restriction ◽  
Whole Body ◽  
Dependent Diabetes Mellitus ◽  
Fed State ◽  
Dietary Protein Restriction ◽  
Sulfate Production ◽  
Before And After

Persons with conventionally treated insulin-dependent diabetes mellitus (IDDM) appear to be impaired in their ability to reduce fed-state urea production appropriately in response to dietary protein restriction (Hoffer LJ, Taveroff A, and Schiffrin A. Am J Physiol 272: E59-E67, 1997). To determine whether these conclusions apply to whole body sulfur amino acid (SAA) catabolism, we used samples from this protocol to measure daily urinary sulfate excretion and fed-state sulfate production after a high-protein test meal before and after dietary protein restriction. Eight normal subjects and six IDDM subjects treated with twice-daily intermediate- and short-acting insulin consumed a mixed test meal containing 0.50 g protein/kg after adaptation to 4 days of high protein intake (1.28 g protein/kg body wt) and again after 5 days of dietary protein restriction (0.044 g/kg). Adaptation to protein restriction decreased daily urinary sulfate and urea-N excretion by ∼80%. Over the first 24 h of protein restriction, urinary sulfate excretion decreased more than urea-N excretion for both the normal and IDDM subjects. Under conditions of a high prior protein intake, fed-state sulfate production was normal for the IDDM subjects; protein restriction reduced fed-state sulfate production by 51% (normal subjects) and 59% (IDDM subjects; not significant). We conclude that whole body SAA metabolism is normal in conventionally treated IDDM before and after dietary protein restriction. SAA catabolism, as measured by fed-state sulfate production, may be a convenient and useful method to determine the extent of whole body protein dysregulation in IDDM.

scholarly journals Whole-body protein turnover in the fed state is reduced in response to dietary protein restriction in lactating women

1996 ◽  
Vol 64 (1) ◽  
pp. 32-39 ◽  
Author(s):  
K J Motil ◽  
T A Davis ◽  
C M Montandon ◽  
W W Wong ◽  
P D Klein ◽  
...  
Keyword(s):  
Dietary Protein ◽  
Protein Turnover ◽  
Protein Restriction ◽  
Whole Body ◽  
Body Protein ◽  
Lactating Women ◽  
Fed State ◽  
Dietary Protein Restriction

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

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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