Chronic high-fat diet induces multi-organ dysfunction and metabolic homeostasis disruption in Macaca fascicularis

The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet (HFD) to mimic clinical disease progression.

Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention. Physiological parameters (BMI, BP, hematology), liver fat fraction (evaluated by ultrasound/MRI), cardiac function (assessed by echocardiography), and histopathology (using liver biopsy) were measured before and after the intervention. Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.

Within 6 months, HFD induced dyslipidemia (elevated TG, TCHO, HDL-C, LDL-C). After 18 months, metabolic dysfunction-associated steatohepatitis (MASH) was confirmed by histopathology in 57.14% (16/28) of macaques, diabetes (elevated FPG/HbA1c) in 17.86% (5/28), and myocardial hypertrophy (elevated LVMass/LAD) in 46.43% (13/28). Proteomics identified Bile acid-CoA: amino acid N-acyltransferase (BAAT) as a MASH hallmark protein, the level of which was inversely correlated with the degree of fibrosis. For diabetes, citrate synthase (CS) and malate dehydrogenase 1 (MDH1) impaired glucose oxidation via the TCA cycle, while hexose-6-phosphate dehydrogenase (H6PD) disrupted gluconeogenesis. Myocardial hypertrophy was associated with the downregulation of SRC proto-oncogene, non-receptor tyrosine kinase (SRC), mitogen-activated protein kinase 14 (MAPK14), emerin (EMD), and integrin subunit beta 1 (ITGB1).

An 18-month HFD successfully established a translational M. fascicularis model replicating key metabolic disorders (MASH, diabetes, cardiac hypertrophy). BAAT, CS/MDH1/H6PD, and SRC/MAPK14/EMD/ITGB1 were identified as mechanistic biomarkers for these conditions.