Journal September 25, 2026 5 min read

What does the research say about metabolic adaptation?

Metabolic adaptation refers to the coordinated physiological and biochemical adjustments that occur in response to altered nutrient availability, energy demand, or dietary composition. This page summarises findings from

peptides-pro Editorial

Metabolic adaptation is the term used for the coordinated set of physiological and biochemical adjustments that occur when an organism encounters altered nutrient availability, energy demand, or dietary composition. In the research literature, it is sometimes referred to as metabolic flexibility or nutrient-driven metabolic remodelling. The concept is not a single molecule or pathway but a systems-level response that can be studied at the level of individual enzymes, hormones, or whole-body energy balance. No single identifier—such as a sequence, formula, or molecular weight—applies to metabolic adaptation as a whole; instead, research focuses on specific mediators and their roles in particular tissues or models.

The work centres on several interconnected pathways, including amino acid–glucose homeostasis via liver glutamate dehydrogenase (GDH), endocrine signalling through fibroblast growth factor 21 (FGF21), mitochondrial-derived peptides (MDPs), and gut–liver–adipose crosstalk involving the microbiota.

Research Studies

Liver GDH and dietary protein source in mice

In a study using control and Hep-Glud1^-/- mice lacking liver GDH, animals were fed either animal- or plant-based diets for four days while macronutrient composition was kept constant. Hepatic GDH was upregulated in control mice eating animal proteins compared to those on the plant regimen. Ad libitum-fed control mice on the plant-based diet had lower glycemia than those on the animal-based diet. The authors concluded that the transition to dietary plant-based proteins requires functional liver GDH for proper control of ammonia and energy homeostasis [1].

HLA-G and tumour-intrinsic growth in renal cell carcinoma

HLA-G is a non-classical MHC class I molecule with immunoregulatory functions. In clear cell renal cell carcinoma (ccRCC), analysis of The Cancer Genome Atlas cohort showed that elevated HLA-G expression was associated with immunosuppressive programmes and cell populations. Single-cell RNA sequencing of a public ccRCC dataset revealed that HLA-G expression within tumour epithelial clusters was associated with hypoxia-related programmes. Integrated in vitro and in vivo approaches supported a tumour-intrinsic role for HLA-G in growth and survival [2].

Hepatic proteomic responses to refeeding in Japanese quail

Eighteen 12-week-old male Japanese quail (Coturnix japonica; 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 24 h low metabolizable energy diet (6.30 MJ/kg) followed by 6 h refeeding. In total, 854 proteins were identified, of which 515 met the filtering criteria. The study characterised early liver protein signatures during recovery from nutritional stress [3].

Lactiplantibacillus plantarum WJL and FGF21 in chronic kidney disease

Low-protein diets (LPD) are recommended in chronic kidney disease (CKD) but carry a risk of protein-energy wasting. In murine models and a randomised controlled trial in nondiabetic CKD patients, LPD improved glucose tolerance and significantly decreased circulating levels of gut-derived uremic toxins while reducing body weight (−33% in one model). The probiotic Lactiplantibacillus plantarum WJL ameliorated CKD by inhibiting the FGF21 adaptive stress response via LPD [4].

Cmpks1 and carotenoid biosynthesis in Cordyceps militaris

In the edible mushroom Cordyceps militaris, the light-induced gene Cmpks1 encodes a reducing type I polyketide synthase. CRISPR/Cas9-mediated loss-of-function mutants exhibited stable albino phenotypes but retained fruiting body differentiation. Disruption of Cmpks1 abolished carotenoid biosynthesis and increased sensitivity to high [stress conditions]. The gene is a key regulator of pigment biosynthesis and metabolic adaptation in this fungus [5].

REV-ERB agonist SR9009 and sorafenib in liver cancer

In hepatocellular carcinoma (HCC), genome-wide RNA-seq identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation. The REV-ERB agonist SR9009 potentiated sorafenib efficacy in liver cancer models, targeting metabolic vulnerabilities [6].

Mitochondria-derived peptides in liver disease

Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA. Humanin, the first MDP discovered, is cytoprotective. MOTS-c regulates metabolic homeostasis and stress adaptation, while SHLP1-6 modulate mitochondrial bioenergetics and insulin sensitivity. MDPs maintain mitochondrial function and metabolic balance in the liver [7].

Probiotic intervention in weight cyclers

A clinical trial (NCT07031596) is evaluating whether probiotics reduce weight regain after caloric restriction by modulating appetite and metabolism. The study background notes that weight regain is common due to metabolic adaptations, and gut microbiota play a critical role in weight management [8].

Adipokine profiles in master athletes

A comparative study examined adipokine profiles in middle-aged master athletes, untrained adults, and young individuals. Adipose tissue is an active endocrine organ involved in metabolic regulation and systemic inflammation, processes altered during aging. The study aimed to characterise the adipokine profile associated with lifelong physical training [9].

Exerkine-mediated inter-organ crosstalk

A review discussed how exercise benefits in obesity and metabolic diseases cannot be fully explained by increased energy expenditure, enhanced skeletal muscle glucose uptake, reduced adiposity, or improved peripheral insulin sensitivity alone. It highlighted exerkine-mediated inter-organ crosstalk [10].

Early hormonal responses after sleeve gastrectomy

A preliminary study evaluated early postoperative changes in the energy-regulating hormones irisin and nesfatin-1 following laparoscopic sleeve gastrectomy in women with obesity. The authors noted that early hormonal changes contributing to metabolic adaptation remain underexplored [11].

Adipose FGF21 signalling and protein restriction

Using genetic loss-of-function models for FGF21 and its obligate co-receptor β-Klotho, a study investigated the mechanisms behind the metabolic health and lifespan benefits of dietary protein restriction. Adipose FGF21 signalling was found to mediate anti-senescence effects [12].

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