Protein Restriction During Pregnancy and Lactation Triggers Steatohepatitis and Adrenal Disorders in Rat Dams: Insights into Maternal Metabolic Health.

A metabolic basis for motor deficits in mice lacking BCKDK.

Placental morphofunctional adaptations and offspring outcomes after protein restriction before and during pregnancy in mice.

Omics-based molecular signatures of adrenal, kidney, and lung development in male rat offspring exposed to maternal protein restriction.

Placental Programming in Maternal Malnutrition as a Crucial Determinant of Offspring Health: A Critical-Interpretative Narrative Review.

Chronic kidney disease is an increasing global public health concern, and the Developmental Origins of Health and Disease (DOHaD) concept proposes that adverse conditions during critical developmental windows predispose offspring to chronic disorders later in life. Maternal protein restriction (MPR), a well-established experimental model reflecting food insecurity, has been shown to impair nephrogenesis and promote long-term renal dysfunction. In this study, we investigated renal metabolic-epigenetic programming induced by gestational and lactational MPR in post-weaning male rats using a global kidney proteomic approach. MPR altered renal structure and profoundly dysregulated protein networks, characterized by downregulation of energy metabolism, ion transport, cytoskeletal organization, membrane integrity, and mitochondrial function, alongside upregulation of innate immune pathways, glutathione metabolism, vesicular trafficking, and cytoskeletal dynamics. Integrated pathway and disease enrichment analyses revealed the potential risk to hypertension, acid-base imbalance, renal tubular transport disorders, nephrosis, and renal failure. Key differentially expressed proteins (e.g., GPX1, CYCS, ATP1A2/ATP1B1, TUBB/TUBA isoforms, ANPEP, and metabolic enzymes) emerged as potential biomarkers of renal metabolic-epigenetic programming. Collectively, these findings identify molecular signatures that link early-life protein restriction to long-term risk of kidney disease and provide mechanistic insight into the nephron- and cell-specific consequences of MPR.

Mapping the evidence: Effects of malnutrition and sarcopenia on fracture healing.

Outcome of Dietary Intervention on Kidney Transplant Recipients With Proteinuria/Chronic Metabolic Acidosis - A Single Cohort Prospective Study.

The effects of maternal broccoli powder (BP) intake on inflammation and AMPK activation in weaning offspring programmed by maternal undernutrition remain poorly understood. This study aimed to investigate whether maternal BP intake during lactation ameliorates inflammation and affects AMPK phosphorylation in the hypothalamus and liver of weaning offspring subjected to maternal undernutrition. Pregnant rats received either a normal protein (NP, 20% casein) or a low protein (LP, 8% casein) diet. During lactation, dams were provided with either a normal protein diet without or with 0.74% BP (NP/NP or NP/NPBP) or a low protein diet without or with 0.74% BP (LP/LP or LP/LPBP). Blood, liver (left lateral lobular region), and hypothalamic samples (region estimated to include the arcuate nucleus and ventromedial hypothalamus) were collected on postnatal day 21. In the liver, macrophage count, NFκB p65 protein expression, and TNF-α mRNA expression were lower in LP/LPBP than in LP/LP. In the hypothalamus, Iba1 mRNA expression, NFκB p65 protein expression, and TNF-α mRNA expression were reduced in LP/LPBP compared to LP/LP. AMPK phosphorylation was upregulated in both the liver and hypothalamus of LP/LPBP offspring relative to LP/LP. In the liver, mTOR and Akt phosphorylation were downregulated in LP/LPBP compared to LP/LP. Additionally, Dnmt1 levels were lower in LP/LPBP than in LP/LP in the liver, whereas in the hypothalamus, Dnmt1 and Dnmt3a mRNA expression levels were higher in NP/NPBP than in NP/NP. In conclusion, maternal BP intake during lactation decreased inflammation and increased AMPK phosphorylation in the liver and hypothalamus of weaning rats programmed by maternal undernutrition.

Abstract Background Isolated Methylmalonic acidaemia (MMA) is a rare inherited metabolic disorder. Nutritional intervention for MMA patients includes dietary restriction of proteins along with medical food and dietary supplements. Decreased bone mineral density (BMD) is a widely accepted complication of protein restricted diet and accumulation of acids and toxic metabolites. Aim of the study To assess bone health in patients with isolated MMA and investigate the contributing factors. Patients and methods The study included all patients biochemically confirmed with isolated MMA above the age of 5 years. Clinical, dietary, and biochemical data were systematically collected. Patient compliance was assessed using author-derived score. Bone mineral density (BMD) was evaluated using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed using serum osteocalcin level, while bone resorption was evaluated using carboxy-terminal telopeptide of collagen type 1 (S-CTX) in addition to selected other bone health laboratory parameters. Results The study included 24 patients. A history of fractures was present in 5 patients (20.83%). Decreased total body BMD was found in 14 patients (54.5 %) with a mean Z score of -1.31 ± 1.38 SD. Decreased spine BMD was present in 21 patients (79.16%) with a mean Z score of -1.9 ± 1.1 SD. This decrease was significantly related to non-compliance, chronic acidosis, disease severity, and low serum copper. There was no significant relation between BMD and creatinine, calcium, vitamin D, zinc, selenium, osteocalcin, or S-CTX levels. Conclusion Isolated MMA patients have defective bone formation and increased bone resorption manifested by decreased BMD and related to poor compliance, chronic acidosis, disease severity and copper deficiency.

Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.

Short-term effects of routine nutritional care on dietary patterns and biochemical parameters in non-dialysis chronic kidney disease patients.

WCN26-5653 Dietary Protein and Salt Restriction in Kidney Transplant Recipients: A Systematic Review and Meta-analysis

We thank Zhao et al.1 for their constructive comments on our recent JASN article, “High Phosphate and Low Protein Mediate Arterial and Cutaneous Vascular Calcification in CKD Mice.”2 We appreciate their thoughtful evaluation of our model and their suggestions to refine mechanistic interpretation and translational relevance. We agree that the pharmacologic specificity of SB203580 deserves consideration. SB203580 is known to selectively inhibit p38α/β while exerting limited effects on p38γ/δ and some off-target kinases at experimental concentrations.3 We chose this inhibitor on the basis of its established efficacy in vascular calcification models and well-characterized pharmacokinetic properties.4 Nonetheless, testing structurally distinct p38 inhibitors and using dominant-negative Mapk14 and smooth muscle–specific, tamoxifen-inducible p38α knockout mice (Myh11-CreERT2/Mapk14fl/fl) would provide important genetic validation. We also appreciate the suggestion to further dissect the synergistic effects of high phosphate and protein restriction. Our initial goal was to reproduce the clinical setting in which patients with CKD often exhibit both hyperphosphatemia and malnutrition. Although we measured aortic fetuin-A and matrix Gla protein, we agree that serial serum monitoring and pair-feeding approaches would clarify how systemic changes in calcification inhibitors and mineral balance parallel tissue mineralization. Moreover, fetuin-A supplementation studies would directly test the causality of the malnutrition–fetuin-A axis. Finally, we acknowledge that our study was limited to male C57BL/6J mice and a 4-week intervention, which may underestimate sex-specific and chronic effects. Future investigations will include both sexes and extended follow-up to capture the full spectrum of vascular and cutaneous pathology. We thank the correspondents again for their insightful feedback, which will help strengthen the mechanistic rigor and translational scope of this experimental platform.

The optimal dietary protein intake (DPI) for patients with chronic kidney disease (CKD) remains uncertain. Long-term, clinical practice data using objective DPI measures are limited, and concerns about nutritional risk persist. To evaluate the association of objectively measured DPI with long-term kidney and clinical outcomes in adults with CKD stages 3 and 4. This retrospective cohort study included adults with CKD stages 3 and 4 receiving care in Clalit Health Services, Israel, with index entry from January 1, 2007, through December 31, 2022, and follow-up of up to 15 years. DPI was assessed using 24-hour urinary nitrogen excretion and normalized to adjusted body weight (normalized DPI [nDPI]). Participants were stratified by an nDPI threshold of 1.0 g/kg/d (selected using time-dependent receiver operating characteristic analysis). Data were analyzed from August to October 2025. nDPI calculated from 24-hour urinary nitrogen excretion, analyzed dichotomously using the 1.0 g/kg/d threshold. The primary outcome was a composite of 50% or more decline in estimated glomerular filtration rate (eGFR), initiation of long-term dialysis, or all-cause mortality. Secondary outcomes included individual components and trajectories of eGFR and albuminuria. Propensity score matching was used to balance baseline characteristics between lower (<1.0 g/kg/d) and higher (≥1.0 g/kg/d) nDPI groups. Kidney function was evaluated using mixed-effects models and joint models linking eGFR trajectories with time-to-event outcomes. Of 1441 included patients (mean [SD] age, 67.20 [11.26] years; 507 [35.2%] women), 530 were matched (265 per group). During follow-up, the lower-nDPI group had a lower risk of the composite outcome (hazard ratio [HR], 0.77; 95% CI, 0.62-0.97; log-rank P = .03), mainly related to fewer dialysis initiations (HR, 0.65; 95% CI, 0.42-0.99). In adjusted Cox models, low nDPI remained associated with lower composite risk (HR, 0.75; 95% CI, 0.60-0.93). Longitudinal models showed no significant between-group differences in eGFR or albuminuria slopes; eGFR decline was numerically slower in the low-nDPI group (slope difference, 0.152 mL/min/1.73 m2/y). No differences in nutritional markers were observed. In this retrospective cohort study of adults with CKD stages 3 and 4, lower nDPI (<1.0 g/kg/d) was associated with lower dialysis risk without nutritional harm. These findings support moderate protein restriction with routine DPI monitoring in CKD care.

We read with great interest the recent study by Jin et al., published in JASN, combining 5/6 nephrectomy with a high-phosphate/low-protein diet to reproduce medial arterial and cutaneous arteriolar calcification and implicate p38 MAPK as a tractable target.1 The rapid, reproducible phenotype and the integration of histology, μCT, and transcriptomics are commendable and create a valuable platform for mechanistic and translational work. However, several methodologic considerations should be addressed to better contextualize the conclusions. First, pharmacologic specificity should be strengthened. Although SB203580 is widely used, it primarily inhibits p38α/β, with limited inhibition of p38γ/δ, and shows relevant off-target kinase inhibition at experimental concentrations.2 We therefore suggest replacing SB203580 with chemically distinct p38 inhibitors (e.g., BIRB-796 [doramapimod], GW856553 [losmapimod], and PH-797804) to test whether the phenotype is reproducible. Given that p38α (Mapk14) is predominant in vascular smooth muscle and its knockdown limits phosphate-induced calcification, we suggest a smooth-muscle–specific, tamoxifen-inducible p38α knockout (SM22α-CreERT2; Mapk14fl/fl) subjected to HPi–Lp+5/6 Nx for genetic validation. Second, the hypothesized synergy whereby malnutrition and hyperphosphatemia amplify calcification has not been directly tested. The authors note that malnutrition may indirectly promote vascular calcification by reducing calcification inhibitors (fetuin-A and matrix Gla protein).3 However, only aortic fetuin-A/matrix Gla protein has been measured without diet-stratified serum trajectories. We recommend an isocaloric pair-feeding or essential amino acid repletion to isolate protein effects from energy deficit. Moreover, we suggest serial measurement of serum fetuin-A and the calcium–phosphate product (Ca×P) during the induction phase, aligned with quantitative readouts of vascular calcium, to clarify how changes in circulating inhibitors and mineral balance track with tissue mineral deposition. Also, an exogenous fetuin-A supplementation (rescue) experiment would directly test the reversibility of the malnutrition–fetuin-A axis in a high-phosphate milieu. Third, generalizability is limited by the use of only male C57BL/6J mice and a short, 4-week exposure that did not reproduce characteristic skin necrosis/pain. Because sex modifies mineral metabolism and vascular remodeling, inclusion of females and longer follow-up would enhance translational relevance.4 In conclusion, the HPi–Lp 5/6 nephrectomy model offers a practical platform for mechanistic investigation and preclinical testing. Clarifying the independent contribution of protein restriction and rigorously establishing p38 as the causal effector would firmly strengthen translational relevance.

FGF21 signals through hindbrain neurons to alter food intake and energy expenditure during dietary protein restriction.

Methylmalonic acidemia (MMA), propionic acidemia (PA), and maple syrup urine disease (MSUD) are rare monogenic disorders that are described as intoxication-type inborn errors of metabolism (IEMs). They usually present in early life, and long-term management requires strict dietary protein restriction, which may significantly alter gut microbiota composition. Despite growing interest in microbiome research, limited data exist on gut microbiota in these disorders, and no study is available for MMA and MSUD. We aimed to describe the gut microbiota compositions in children with MMA, PA, and MSUD. A total of eight patients (Five MMA, one PA, and two MSUD), and 11age-matched healthy controls were enrolled. All patients were following a medically supervised, protein-restricted diet. Fecal sample was collected from each participant, and gut microbiota composition was evaluated with 16S rRNA sequencing. Patients with MMA, PA, and MSUD exhibited significantly altered gut microbiota composition compared to healthy controls. Alpha diversity analysis revealed reduced microbial richness in patients, with significantly lower Chao1 and observed OTU indices (p < 0.05). Beta diversity metrics demonstrated distinct clustering between groups, indicating significantly different microbial community structures. Higher relative abundances of opportunistic or dysbiotic taxa have been seen in patient group, while controls were enriched in beneficial taxa like Faecalibacterium prausnitzii, Ruminococcus, and Lactobacillus. LEfSe analysis identified 17 taxa enriched in patients-including members of Proteobacteria, Sphingobacteriia, and Streptococcus anginosus-and 6 taxa enriched in controls, notably Faecalibacterium prausnitzi. This is the first descriptive study of the gut microbiota composition of MMA, PA, and MSUD patients. These findings indicate an association between long-term dietary management and altered microbiota composition, although causality cannot be inferred due to the cross-sectional study design. The observed alterations suggest that the gut microbiota may represent a novel therapeutic target in the management of IEMs.

Nutritional awareness is a significant challenge for patients with chronic liver diseases (CLD), especially for those with conditions such as ascites, hepatic encephalopathy, and fatty liver disease. This survey aims to assess nutritional awareness regarding liver disease among healthcare providers (hepatologists and non-hepatologists). A structured online questionnaire was created based on clinical knowledge and established guidelines related to nutrition in liver disease. The survey consisted of 13 questions addressing nutritional considerations for liver disease patients. A total of 124 out of 362 survey recipients responded. Among them, 60.5% were hepatologists, while the remaining respondents included general practitioners, endocrinologists, and cardiologists. Hepatologists were more likely than non-hepatologists to recognize the significance of nutritional guidance for their patients, with 74.7% of hepatologists supporting this view compared to only 40.8% of non-hepatologists (p < 0.001). For patients with compensated cirrhosis, 82.7% of hepatologists preferred no dietary restrictions, whereas only 46.9% of non-hepatologists agreed (p < 0.001). Both groups favored protein restriction in cases of hepatic encephalopathy, (p = 0.2). Regarding patients with ascites, both hepatologists and non-hepatologists recommended salt restriction, with hepatologists showing a stronger inclination. When it comes to alcohol consumption, 80% of hepatologists and 61.2% of non-hepatologists favored restricting alcohol intake in patients with chronic liver disease (p = 0.03). There are notable differences in nutritional priorities and recommendations between hepatologists and non-hepatologists. There is a pressing need to raise awareness among non-hepatologist physicians concerning dietary recommendations for patients with chronic liver disease.

Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.