Dietary Protein Restriction Research Articles

Hepatic encephalopathy approach: Pharmacological therapy

Introduction: Hepatic encephalopathy is a neuropsychiatric complication that occurs in patients with advanced liver disease, resulting in a variety of neurological and psychiatric symptoms. Effective treatment is of paramount importance due to the morbidity associated with this condition. Objective: This study aims to review current therapeutic approaches for hepatic encephalopathy, highlighting common treatment strategies and future prospects for therapeutic intervention. Methodology: The review was conducted by searching scientific databases, including relevant clinical trials, to identify therapeutic strategies used in hepatic encephalopathy. Results: Common therapeutic approaches for hepatic encephalopathy include dietary protein restriction, the use of Lactulose for ammonia excretion, and the administration of antibiotics such as rifaximin to reduce ammonia-producing intestinal flora. Various research efforts are underway to discover future pharmacological therapies. Conclusion: The therapeutic approach to hepatic encephalopathy is multifaceted, aiming to alleviate acute symptoms and prevent recurrences. A multidisciplinary strategy is essential for the effective management of this complex condition, and ongoing research is exploring new therapies that may improve the prognosis and quality of life for affected patients. Understanding the pathophysiology of hepatic encephalopathy is evolving, offering hope for more effective treatments in the future.

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD.We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records.A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6–24) and 66 months (35–156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues.LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Prolonged dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis

Prolonged dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis

Dietary protein restriction modulates ‘dessert’ intake after a meal, via fibroblast growth factor 21 (FGF21)

Pharmacological administration of fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load diet could reduce the consumption of sweet desserts in sated mice. Here, we tested the prediction that individuals maintained on a low P: E diet, and offered a highly palatable sweet ‘dessert’ following a pre-load meal, would eat less of the sugary snack compared to controls—due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals maintained on the low P: E diet, and offered a very high-protein pellet as ‘dessert’ or snack after a meal, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21ΔL) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21ΔL mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load diet is not sufficient to reduce the consumption of sweet desserts, though it effectively increases the subsequent intake of dietary protein in male mice.

Nutritional programming in Nile tilapia (Oreochromis niloticus): Effect of low dietary protein on growth and the intestinal microbiome and transcriptome.

Nutritional programming is the idea that early nutrient contributions can influence organismal structure or function and is documented in a variety of vertebrates, yet studies in fish are largely lacking. Tilapia are an important foodfish, with global production having increased rapidly since the 1990s. They exhibit high disease-resistance and grow well on formulated feeds which makes them an ideal aquaculture species, however incorporating high quality proteins into feeds can be costly. As feed constitutes 50-70% of total production costs in aquaculture, reducing protein content could curb these costs and increase revenue. Thus, we examined the effects of feeding Nile tilapia (O. niloticus) fry a restricted protein diet for the first 7-21 days on growth, gut microbial flora, and the intestinal transcriptome. Fish were fed either a 25% restricted or 48% control crude protein starter (ST) diet for up to 21 days and then switched to a 25% or 38% control crude protein growout (GO) diet. Fish fed a 25% ST diet for 14 days followed by a 38% GO diet had significantly higher lengths and weights and better feed efficiency than fish fed the control 48% ST and 38% GO diet after 56 days of culture. Growth of fry on the 25% ST, 7-day/38% GO and the 25% ST,7-day/25% GO diets did not differ from the those fed the control protein diets, while fish fed the 25% ST diet for 21 days had significantly lower growth and survival rates. We observed no significant differences in either alpha or beta diversity of the gut microbial flora between diets, however species richness (Shannon Index) was higher in fry fed the 25% protein ST diet regardless of the GO diet. Similarly, fish fed the 25% ST diet for 14 days followed by the 38% GO diet had minimal changes to the intestinal transcriptome relative to fish fed the control 48% ST and 38% GO diet. However, those fed 25% ST and GO diets for the entire 56 days exhibited substantial differences in the gut transcriptome from other groups showing gene expression profiles characteristic of detrimental changes to gut physiology, protein metabolism and immune function. Results suggest protein restriction for up to 14 days early in development leads to enhanced growth and feed efficiency with minimal effects on gut microbes or intestinal function. Protein restriction beyond this period appears detrimental to fish growth and health as underscored by expression of disease related genes and higher mortality rates.

Malformação arterioportal hepática em um cão - relato de caso

ABSTRACT Arterioportal communications are complex hepatic vascular abnormalities. These are rarely seen in dogs and typically manifest as neurological, gastrointestinal, and developmental changes. This report describes clinical, laboratory and imaging findings associated with hepatic arterioportal malformation in a male Shih-Tzu dog aged 12 months. The diagnosis was achieved using computed tomographic angiography. The therapeutic approach selected consisted of palliative medical management (diuretics) combined with dietary protein restriction (3.6 g/100 kcal) provided by hepatic diet and gut activity modulation using lactulose. Surgical intervention was not recommended due to the complexity of vascular changes and portal hypertension. Despite initial clinical improvement, the patient died of disease-related complications seven months after diagnosis. Computed tomographic angiography was vital for accurate diagnosis and treatment selection, that needs to be more investigated.

Health-related quality of life in a european sample of adults with early-treated classical PKU

BackgroundPhenylketonuria (PKU) is a rare inborn error of metabolism affecting the catabolism of phenylalanine (Phe). To date, findings regarding health-related quality of life (HRQoL) in adults with early-treated classical PKU are discrepant. Moreover, little is known about metabolic, demographic, and cognitive factors associated with HRQoL. Hence, we aimed to investigate HRQoL and its association with demographic, metabolic, and cognitive characteristics in a large European sample of adults with early-treated classical PKU.ResultsThis cross-sectional study included 124 adults with early-treated classical PKU from Hungary, Italy, Spain, Switzerland, and Turkey. All participants prospectively completed the PKU quality of life questionnaire (PKU-QoL), a questionnaire specifically designed to evaluate the impact of PKU and its treatment on HRQoL in individuals with PKU. In addition, information about Phe levels (concurrent and past year), demographic (age and sex), and cognitive variables (intelligence quotient, IQ) were collected. Most domains revealed little or no impact of PKU on HRQoL and more than three-quarters of the patients rated their health status as good, very good, or excellent. Nevertheless, some areas of concern for patients were identified. Patients were worried about the guilt that they experience if they do not adhere to the dietary protein restriction and they were most concerned about high Phe levels during pregnancy. Further, tiredness was the most affected symptom, and the supplements’ taste was considered a main issue for individuals with PKU. The overall impact of PKU on HRQoL was higher in women (U = 1315.5, p = .012) and in adults with a lower IQ (rs = − 0.448, p = .005). The overall impact of dietary protein restriction was higher in adults with higher concurrent Phe levels (rs = 0.272, p = .007) and higher Phe levels during the past year (rs = 0.280, p = .009).ConclusionThe impact of PKU on most domains assessed in the PKU-QoL was considered to be low. These results likely reflect the successful implementation of the newborn screening resulting in the prevention of severe adverse long-term outcomes. However, a particular clinical focus should be given to patients with lower IQ, higher Phe levels, and women, as these variables were associated with a lower HRQoL.

The Microbiome and Protein Carbamylation: Potential Targets for Protein-Restricted Diets Supplemented with Ketoanalogues in Predialysis Chronic Kidney Disease.

In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation.

66. Variation in protein efficiency as assessed by DXA in barrows fed a protein-restricted diet

66. Variation in protein efficiency as assessed by DXA in barrows fed a protein-restricted diet

Citrulline in the management of patients with urea cycle disorders

BackgroundTreatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes.ResultsOverall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions.ConclusionsThis study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations.

Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.5 and 2 per million live births. On the basis of small case series and sibling data, presymptomatic treatment with oral supplements of creatine, ornithine, and sodium benzoate, and a protein-restricted diet to reduce arginine intake, appear to substantially improve health and developmental outcomes. Without newborn screening, diagnosis typically happens after the development of significant impairment, when treatment has limited utility. GAMT deficiency newborn screening can be incorporated into the tandem-mass spectrometry screening that is already routinely used for newborn screening, with about 1 per 100 000 newborns screening positive. After a positive screen, diagnosis is established by finding an elevated guanidinoacetate concentration and low creatine concentration in the blood. Although GAMT deficiency is significantly more rare than other conditions included in newborn screening, the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023.

Fasting and non-fasting plasma levels of monomethyl branched chain fatty acids: Implications for maple syrup urine disease.

The branched-chain amino acids (BCAA) leucine, valine, and isoleucine provide precursors for monomethyl branched-chain fatty acids (BCFA). Established reference ranges for BCFAs are lacking. In maple syrup urine disease (MSUD), a rare inborn error of BCAA metabolism, the endogen production is impaired and MSUD patients are treated with a low protein (low BCAA) diet. The protein restriction may affect the dietary intake of BCFA, depending on the dietary choices made. Patients with MSUD are prescribed a more or less protein-restricted diet depending on the severity of the disease. The combination of a protein-restricted diet and subsequent impaired endogenous synthesis may render MSUD patients sensitive to BCFA deficiency, with yet unknown implications. To investigate the possibility of lower circulatory BCFA levels in MSUD that favors dietary BCFA supplementation, we first established fasting-state reference ranges for selected BCFAs and saturated/unsaturated fatty acids in plasma. Then, the effect of fasting on BCFA levels was evaluated by comparing the distribution in a fasting versus a non-fasting cohort. To test the hypothesis that BCFA deficiency could contribute to MSUD pathophysiology, we recruited patients with intermittent, intermediate, and classical form of MSUD and analyzed the corresponding BCFA z-scores. None of the BCFA species had |z-scores| > 2 relative to the reference range. Our findings do not support the requirement of BCFA supplementation in MSUD patients. The origin of BCFAs is discussed. Impaired capacity to synthesize BCFA do not manifest as reduced plasma levels in MSUD, suggesting that endogenous synthesis is dispensable for plasma levels.

Dietary Protein Regulates Female Estrous Cyclicity Partially via Fibroblast Growth Factor 21.

Fibroblast growth factor 21 (FGF21), a hormone predominantly released in the liver, has emerged as a critical endocrine signal of dietary protein intake, but its role in the control of estrous cyclicity by dietary protein remains uncertain. To investigated the role of FGF21 and hypothalamic changes in the regulation of estrous cyclicity by dietary protein intake, female adult Sprague-Dawley rats with normal estrous cycles were fed diets with protein contents of 4% (P4), 8% (P8), 13% (P13), 18% (P18), and 23% (P23). FGF21 liver-specific knockout or wild-type mice were fed P18 or P4 diets to examine the role of liver FGF21 in the control of estrous cyclicity. Dietary protein restriction resulted in no negative effects on estrous cyclicity or ovarian follicular development when the protein content was greater than 8%. Protein restriction at 4% resulted in decreased bodyweight, compromised Kiss-1 expression in the hypothalamus, disturbed estrous cyclicity, and inhibited uterine and ovarian follicular development. The disturbed estrous cyclicity in rats that received the P4 diet was reversed after feeding with the P18 diet. Liver Fgf21 mRNA expressions and serum FGF21 levels were significantly increased as dietary protein content decreased, and loss of hepatic FGF21 delayed the onset of cyclicity disruption in rats fed with the P4 diet, possibly due to the regulation of insulin-like growth factor-1. Collectively, severe dietary protein restriction results in the cessation of estrous cyclicity and ovarian follicle development, and hepatic FGF21 and hypothalamic Kiss-1 were partially required for this process.

Zinc Enhancement through Supplementation and Dietary Implementation – Does It Affect Oxidative Stress and Antioxidant Status in Chronic Kidney Disease Patients?

Background: Chronic kidney disease (CKD) patients might be zinc deficient due to compromised nutritional intake and dietary protein restrictions; protein foods being rich in zinc. Zinc deficiency might cause increased oxidative stress and consequently reduced antioxidant parameters. Tailored dietary counseling along with zinc supplementation may play a major role in affecting the zinc and antioxidant status of patients. Aim: The aim of this study was to investigate the effect of zinc supplementation and dietary counseling on oxidative stress and antioxidant parameters in CKD patients. Materials and Methods: 185 subjects were enrolled for the study (145 were predialysis patients [Group-1 (Stage-3 CKD) and Group-2 [Stage-4 CKD]) on the basis of Kidney Disease Outcomes Quality Initiative CKD stages from 1 to 5; and 40 apparently healthy controls. Zinc supplementation alone (Intervention 1) was given to 50 CKD patients (30 Group-1 and 20 Group-2). Diet counseling (Intervention 2) consisted of 45 patients (25 Group-1; 20 Group-2). 50 patients (30 Group-1 and 20 Group-2) received both zinc supplementations along with diet counseling (Intervention 3). Dietary zinc status, oxidative stress and antioxidants were accessed for all subjects. Results: Intervention-1 and 3 groups exhibited highly significant improvement in antioxidant status and lowering of oxidative stress. Conclusion: Improving zinc status through dietary counseling and supplementation may help in combating enhanced oxidative stress by improving antioxidant parameters in renal failure patients.

OR12-05-23 The Impact of Maternal Protein Restriction and High-Fat Diet in Offspring on the Outcomes of Growth Hormone Treatment in Mice

OR12-05-23 The Impact of Maternal Protein Restriction and High-Fat Diet in Offspring on the Outcomes of Growth Hormone Treatment in Mice

What is central to renal nutrition: protein or sodium intake?

Historically, nutrition intervention has been primarily focused on limiting kidney injury, reducing generation of uraemic metabolites, as well as maintaining nutrition status and preventing protein-energy wasting in patients with chronic kidney disease (CKD). This forms an important rationale for prescribing restricted protein diet and restricted salt diet in patients with CKD. However, evidence supporting a specific protein intake threshold or salt intake threshold remains far from compelling. Some international or national guidelines organizations have provided strong or 'level 1' recommendations for restricted protein diet and restricted salt diet in CKD. However, it is uncertain whether salt or protein restriction plays a more central role in renal nutrition management. A key challenge in successful implementation or wide acceptance of a restricted protein diet and a restricted salt diet is patients' long-term dietary adherence. These challenges also explain the practical difficulties in conducting randomized trials that evaluate the impact of dietary therapy on patients' outcomes. It is increasingly recognized that successful implementation of a restricted dietary prescription or nutrition intervention requires a highly personalized, holistic care approach with support and input from a dedicated multidisciplinary team that provides regular support, counselling and close monitoring of patients. With the advent of novel drug therapies for CKD management such as sodium-glucose cotransporter-2 inhibitors or non-steroidal mineralocorticoid receptor antagonist, it is uncertain whether restricted protein diet and restricted salt diet may still be necessary and have incremental benefits. Powered randomized controlled trials with novel design are clearly indicated to inform clinical practice on recommended dietary protein and salt intake threshold for CKD in this new era.

Genetic analysis of protein efficiency and its association with performance and meat quality traits under a protein-restricted diet

BackgroundAn essential component in the development of sustainable pig production is the reduction of nitrogen excretion in fattening pigs. Pig feeds typically contain high levels of dietary crude protein, and due to incomplete conversion to muscle tissue, excess nitrogen is excreted, resulting in environmental problems such as nitrate pollution and greenhouse gas emissions. Therefore, improving protein efficiency (PE), i.e., the proportion of dietary protein that remains in the carcass, is desirable. The aim of this study was to estimate the heritability (h2) of PE and its genetic correlations with phosphorus efficiency, three performance, seven meat quality and two carcass quality traits when pigs were fed a 20% protein-restricted diet, using 1071 Swiss Large White pigs. To determine PE, the intake of feed with known nutrient content was accurately recorded for each pig and the nitrogen and phosphorus content of the carcass was determined using dual-energy X-ray absorptiometry.ResultsWe found an average PE of 0.39 ± 0.04 and a heritability of 0.54 ± 0.10. PE showed a high genetic correlation with phosphorus efficiency (0.61 ± 0.16), moderate genetic correlations with feed conversion ratio (− 0.55 ± 0.14) and average daily feed intake (− 0.53 ± 0.14), and a low genetic correlation with average daily gain (− 0.19 ± 0.19). While PE has favourable genetic correlations with the performance traits and some meat quality traits, there is a potentially unfavourable correlation of PE with meat colour (redness [rg = − 0.27 ± 0.17]; yellowness [rg = − 0.31 ± 0.18]) and intra-muscular fat (IMF; rg = − 0.39 ± 0.15). Feed conversion ratio (FCR) also showed unfavourable genetic correlations with meat lightness, redness yellowness, IMF and cooking loss.ConclusionsPE is a heritable trait that can be considered in breeding programs to reduce the environmental impact of pig production. We found no strong negative correlation of PE with meat quality traits, and that there is potential to indirectly select for improved phosphorus efficiency. Selecting nutrient efficiencies might be a more suitable strategy to reduce nitrogen pollution from manure than focusing on FCR because the latter also shows genetic antagonism with some meat quality traits in our population.

BENEFICIAL EFFECTS OF PROTEIN RESTRICTION ON METABOLIC HEALTH, COGNITIVE FUNCTION AND NEUROPATHOLOGY IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

AbstractBackgroundAge is the greatest risk factor in developing Alzheimer’s Disease (AD); hence, there is great interest in the possibility of targeting AD through interventions that slow or delay aging. Dietary protein restriction (PR) has been shown to be beneficial in improving overall healthspan in both humans and mice. However, the effect of PR in delaying the symptom progression of AD is largely unknown. In this study, we sought to determine the effects of PR in improving metabolic dysfunction, cognitive deficits and AD pathology along with examining the role of mTORC1 and its downstream targets in the 3xTg mouse model of AD.MethodSix month old male and female 3xTg‐AD mice were placed on either 21% protein (control) or 7% protein (PR) diets starting from 6 months and continued until 15 months to determine their effects on cognition, metabolic health and AD neuropathology. Cognitive functioning was assessed via Novel Object Recognition (NOR) test and Barnes maze test.ResultFemale 3xTg‐AD mice on PR diet showed improved long‐term memory (LTM), and males showed a positive trend in improved cognitive function compared with their age matched controls. Based on latency measurements in Barnes maze, we found that a PR diet substantially improved spatial memory in both male and female 3xTg mice. Female and male mice on low protein diets exhibited improvement in glucose tolerance, however females showed a stronger effect in glycemic control than males following a glucose tolerance test (GTT). Histopathological analysis of the hallmarks of AD showed that mice on PR had decreased tau phosphorylation and Aß plaques. Phosphorylation of the mTORC1 substrate S6K1 was decreased in PR fed 3xTg mice which suggest that reduced mTORC1 signaling may be mediating the beneficial effects of PR on AD pathology. We also found that levels of p62 protein, the major autophagy cargo receptor, is increased in 3xTg AD mice and following PR, decreased p62 expression was observed, suggesting that PR activates autophagy.ConclusionThese results suggests the molecular interplay between mTORC1 and autophagy in PR mediated beneficial effects in diminishing AD pathology.

Association of NAFLD with FGF21 Polygenic Hazard Score, and Its Interaction with Protein Intake Level in Korean Adults.

Fibroblast growth factor 21 (FGF21) is a hormone that participates in the regulation of energy homeostasis and is induced by dietary protein restriction. Preclinical studies have suggested that FGF21 induction exerts a protective effect against non-alcoholic fatty liver disease (NAFLD), while human studies have revealed elevated levels of and potential resistance to FGF21 in patients with NAFLD. However, whether the FGF21 pathway also contributes to NAFLD risk at the genetic level remains uncertain. A few attempts to investigate the impact of individual genetic variants at the loci encoding FGF21 and its receptors on NAFLD risk have failed to establish a clear association due to a limited effect size. Therefore, this study aimed to (1) develop a polygenic hazard score (PHS) for FGF21-related loci that are associated with NAFLD risk and (2) investigate the effect of its interaction with protein intake level on NAFLD risk. Data on 3501 participants of the Korean Genome Epidemiology Study (Ansan-Ansung) were analyzed. Eight single-nucleotide polymorphisms of fibroblast growth factor receptors and beta-klotho were selected for PHS determination using forward stepwise analysis. The association between the PHS and NAFLD was validated (p-trend: 0.0171 for men and <0.0001 for women). Moreover, the association was significantly modulated by the protein intake level in all participants as well as women (p-interaction = 0.0189 and 0.0131, respectively) but not in men. In particular, the women with the lowest PHS values and a protein intake lower than the recommended nutrient intake (RNI) exhibited a greater NAFLD risk (HR = 2.021, p-trend = 0.0016) than those with an intake equal to or greater than the RNI; however, those with higher PHS values had a high risk, regardless of protein intake level. These findings demonstrate the contribution of FGF21-related genetic variants and restricted protein intake to NAFLD incidence.

Protein restriction during peripubertal period impairs endothelial aortic function in adult male Wistar rats.

Protein restriction during early phases of body development, such as intrauterine life can favor the development of vascular disorders. However, it is not known if peripubertal protein restriction can favor vascular dysfunction in adulthood. The present study aimed to evaluated whether a protein restriction diet during peripubertal period favors endothelial dysfunction in adulthood. Male Wistar rats from postnatal day (PND) 30 until 60 received a diet with either 23% protein (CTR group) or with 4% protein (LP group). At PND 120, the thoracic aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in the presence or absence of: endothelium, indomethacin, apocynin and tempol. The maximum response (Rmax) and pD2 (-log of the concentration of the drug that causes 50% of the Rmax) were calculated. The lipid peroxidation and catalase activity were also evaluated in the aorta. The data were analyzed by ANOVA (one or two-ways and Tukey's) or independent t-test; the results were expressed as mean ± S.E.M., p < 0.05. The Rmax to phenylephrine in aortic rings with endothelium were increased in LP rats when compared with the Rmax in CTR rats.Apocynin and tempol reduced Rmax to phenylephrine in LP aortic rings but not in CTR. The aortic response to the vasodilators was similar between the groups. Aortic catalase activity was lower and lipid peroxidation was greater in LP compared to CTR rats. Therefore, protein restriction during the peripubertal period causes endothelial dysfunction in adulthood through a mechanism related to oxidative stress.