Journal September 25, 2026 7 min read

How Does Metabolic Adaptation Work?

Metabolic adaptation describes the coordinated shift in hepatic, endocrine and mitochondrial signalling that follows a change in nutrient supply. This page summarises laboratory research on the mechanisms involved, inclu

peptides-pro Editorial

Metabolic adaptation is the term used for the coordinated set of biochemical and transcriptional adjustments an organism makes when nutrient supply, energy demand or dietary composition changes. In the research literature it is studied under several related labels, including nutrient-stress adaptation, refeeding response, dietary protein adaptation and metabolic remodelling. It is not a single molecule or a single pathway; it is a systems-level response observed across liver, adipose tissue, skeletal muscle, gut microbiota and the endocrine system. The evidence summarised here comes from murine models, avian models, fungal genetics, cell culture and human trials, and each study is identified by the model in which the finding was made.

The work described below centres principally on hepatic amino-acid and glucose handling, the fibroblast growth factor 21 (FGF21) endocrine axis, mitochondria-derived peptides (MDPs) encoded by small open reading frames within mitochondrial DNA, and the REV-ERB nuclear receptor family.

Research Studies

Liver glutamate dehydrogenase and dietary protein source in mice

Glutamate dehydrogenase (GDH), encoded by Glud1, bridges amino-acid catabolism and glucose homeostasis in the liver. In a study using control mice and Hep-Glud1^-/- mice lacking liver GDH, animals were fed either animal-based or plant-based diets for four days while the macronutrient spectrum was held constant. Hepatic GDH was upregulated in control mice eating animal proteins relative to those on the plant regimen. Ad libitum-fed control mice on the plant-based regimen showed lower glycemia than those on the animal regimen. The authors concluded that a transition to dietary plant-based proteins requires functional liver GDH for proper control of ammonia and energy homeostasis [1].

Hepatic proteomic recovery after refeeding in Japanese quail

Feed intake and refeeding after nutrient scarcity drive rapid metabolic adaptation in the poultry liver. In a proteomic study, eighteen 12-week-old male Japanese quail (Coturnix japonica), mean body mass 245.20 ± 0.213 g, were assigned to three groups (n = 6): control fed ad libitum (12.13 MJ/kg), 24 h feed deprivation followed by 6 h refeeding, and a 24 h low metabolizable energy diet (6.30 MJ/kg) followed by 6 h refeeding. A total of 854 proteins were identified, of which 515 met the filtering criteria. The study aimed to characterise early liver protein signatures in the hours immediately after refeeding [3].

Low-protein diet, FGF21 and gut microbiota in chronic kidney disease

Low-protein diets (LPD) are recommended in chronic kidney disease (CKD) to slow progression, but their efficacy and safety are debated because of the risk of protein-energy wasting. A study examined the metabolic effects of LPD in murine models and in a randomised controlled trial in non-diabetic CKD patients, focusing on glucose homeostasis, plasma uremic toxin levels, gut microbiota remodelling and endocrine adaptation. In both the experimental and clinical settings, LPD improved glucose tolerance and significantly decreased circulating gut-derived uremic toxins while reducing body weight by 33% in the experimental setting. The authors further reported that Lactiplantibacillus plantarum WJL ameliorated CKD in the murine model by inhibiting the FGF21 adaptive stress response under low-protein diet conditions [4].

Adipose FGF21 signalling and protein restriction

Dietary protein restriction is a recognised nutritional intervention reported to enhance metabolic health and extend lifespan, though the mechanisms are incompletely understood. Using genetic loss-of-function models for FGF21 and its obligate co-receptor β-Klotho, this work examined whether adipose FGF21 signalling mediates the anti-senescence effects of protein restriction [12].

Mitochondria-derived peptides in hepatic metabolism

Mitochondria-derived peptides are bioactive molecules encoded by small open reading frames within mitochondrial DNA. Humanin, the first MDP discovered, acts as a cytoprotective factor that protects cells from stress-induced apoptosis. The family also includes Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), described as a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1-6), which modulate mitochondrial bioenergetics and insulin sensitivity. In the liver, MDPs contribute to homeostasis by maintaining mitochondrial function and metabolic balance, and intracellularly they modulate mitochondrial signalling [7].

REV-ERB agonism and oxidative phosphorylation in liver cancer models

Hepatocellular carcinoma (HCC) has a poor prognosis, with median survival of 12–15 months in patients with advanced-stage disease. Genome-wide RNA-seq analysis identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation as features of the tumour metabolic programme. Against this background, the REV-ERB agonist SR9009 was investigated for its capacity to potentiate sorafenib efficacy in liver cancer models [6].

Cmpks1 and carotenoid biosynthesis in Cordyceps militaris

Cordyceps militaris produces orange-yellow fruiting bodies primarily through carotenoid accumulation. The gene Cmpks1, a light-induced gene encoding a reducing type I polyketide synthase, was identified as a key regulator of pigment biosynthesis. Its transcription was CmWC-1-dependent and upregulated during fruiting body development. CRISPR/Cas9-mediated loss-of-function mutants of Cmpks1 showed stable albino phenotypes while retaining fruiting body differentiation. Beyond abolishing carotenoid biosynthesis, disruption of Cmpks1 increased sensitivity to high [5].

HLA-G as a tumour-intrinsic factor in renal cell carcinoma

HLA-G is a non-classical MHC class I molecule with immunoregulatory functions that is aberrantly expressed in multiple malignancies. To characterise its tumour-intrinsic role in clear cell renal cell carcinoma (ccRCC), a study combined transcriptomic, in vitro and in vivo approaches. Analysis of the Cancer Genome Atlas ccRCC cohort showed that elevated HLA-G expression was associated with immunosuppressive programmes and cell populations. Interrogation of a public ccRCC single-cell RNA sequencing dataset indicated that HLA-G expression within tumour epithelial clusters is associated with hypoxia-related programmes [2].

Probiotic intervention and weight regain after caloric restriction

Obesity is a chronic disease linked to cardiovascular disease, hypertension and diabetes. Current treatments focus on weight loss through dietary control and exercise, but weight regain is common because of metabolic adaptations that follow caloric restriction. Gut microbiota are recognised as playing a role in weight management, and probiotics have been proposed as a means of reducing weight regain by modulating appetite and metabolism. A registered clinical trial is evaluating the potential of a probiotic preparation in obesity management, specifically its impact on weight cyclers [8].

Adipokine and hormonal responses in human cohorts

Adipose tissue functions as an active endocrine organ involved in metabolic regulation and systemic inflammation, processes altered during ageing; the adipokine profile associated with lifelong physical training in master athletes has been compared with that of untrained adults and young individuals [9]. Separately, a review examined exerkine-mediated inter-organ crosstalk, noting that the systemic benefits of exercise cannot be fully explained by increased energy expenditure, enhanced skeletal muscle glucose uptake, reduced adiposity or improved peripheral insulin sensitivity alone [10]. A preliminary study evaluated early postoperative changes in the energy-regulating hormones irisin and nesfatin-1 following laparoscopic sleeve gastrectomy in women with obesity [11].

Comparison of models and reported adaptations

Model / population	Intervention or condition	Reported adaptation	Source
Control and Hep-Glud1^-/- mice	4 days animal- vs plant-based diet	Hepatic GDH upregulated on animal protein; lower glycemia on plant regimen in controls	[1]
Male Japanese quail	24 h feed deprivation or low-ME diet, then 6 h refeeding	854 proteins identified; 515 met filtering criteria	[3]
Murine models and non-diabetic CKD patients	Low-protein diet	Improved glucose tolerance; reduced gut-derived uremic toxins; 33% body weight reduction in the experimental setting	[4]
HCC models	REV-ERB agonist SR9009 with sorafenib	OxPhos and Hmox1 identified by RNA-seq as targetable features	[6]
ccRCC cohort and cell models	HLA-G expression analysis	Elevated HLA-G associated with immunosuppressive programmes; epithelial HLA-G linked to hypoxia	[2]

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