What question did this study set out to answer?

The study aims to evaluate the effects of a short-term high-fat diet on insulin resistance and associated metabolic pathways in humans.

June 7, 2026

2448-P: Short-Term Hypercaloric High-Fat Diet Feeding Induces White Adipocyte Insulin Resistance in Humans by Activation of the Protein Kinase cε Pathway

Key Points

The study aims to evaluate the effects of a short-term high-fat diet on insulin resistance and associated metabolic pathways in humans.
Randomized, parallel-group study with glucose-tolerant participants (N=10) consuming an isocaloric diet or a hypercaloric high-fat diet for 3 weeks.
Assessment of insulin sensitivity via hyperinsulinemic-euglycemic clamp and measurement of hepatic lipid content by 1H-MRS.
Evaluation of PKCε translocation and Akt phosphorylation in white adipose tissue biopsies.
Adipose tissue insulin resistance increased with the hypercaloric high-fat diet (HFD) compared to isocaloric diet (ICD) (p=0.026).
Basal membrane-to-cytosol PKCε increased significantly after HFD (p=0.008).
Insulin-stimulated Akt phosphorylation decreased with HFD (p=0.004), indicating impaired insulin signaling.

Abstract

Introduction and Objective: High-fat diet (HFD) is known to induce insulin resistance (IR). Studies in rodents suggest that protein kinase C (PKC) ε translocation in white adipose tissue (WAT) occurs early in HFD-induced IR. In order to examine this question in humans, we measured PKCε translocation and basal and insulin-stimulated Akt phosphorylation in WAT biopsies after 3-weeks of an isocaloric diet (ICD) or a hypercaloric HFD. Methods: In a randomized, parallel-group study, glucose-tolerant participants (2 women and 8 men, aged 28±2 years, body mass index 25.9±1.1 kg/m2) consumed either an ICD (55% carbohydrates, 15% protein, 30% lipids) or a hypercaloric HFD (ICD + 40% of total calories as lipids) for 3 weeks. Whole-body insulin sensitivity (M-value) was assessed by a hyperinsulinemic-euglycemic clamp and hepatic lipid (HL) content was measured by 1H-magnetic resonance spectroscopy. Adipose tissue IR (Adipo-IR) was calculated from fasting insulin and non-esterified fatty acids. WAT biopsies were obtained during fasting and insulin stimulation. PKCε translocation and insulin-stimulated Akt phosphorylation were assessed by western blot as membrane-to-cytosol (M/C) PKCε and pAkt/Akt ratios. Results: Neither the M-value: (-0.65±0.41 vs. +0.35±0.52 mg·kg²·min², p=0.146) or the HL content (-0.17±0.45% vs. 0.23±0.32%, p=0.323) changed during HFD and ICD, while Adipo-IR increased only with HFD (+1.10±0.57 vs. -0.24±0.55 mmol·mU/L², p=0.026). After the HFD basal M/C PKCε increased (+3.46±0.62 vs. -0.66±0.37 a.u., p=0.008) and insulin-stimulated pAkt/Akt decreased (-0.43±0.11 vs. +0.09±0.13 a.u., p=0.004). Circulating pro-inflammatory markers remained unchanged in both groups (p=0.128). Conclusion: Short-term HFD primarily impairs WAT insulin sensitivity through enhanced PKCε translocation in line with activation of the sn-1,2-DAG-PKCε-IRS-Thr¹¹60 phosphorylation pathway, suggesting a key role of this pathway in the early pathogenesis of overfeeding-induced IR. Disclosure G. Xourafa: None. D. Zhang: None. C. Granata: None. S. Trenkamp: None. V. Schrauwen-Hinderling: None. J. Schweinitzer: None. M. Huttasch: None. K. Petersen: Research Support; Current; Merck Current; Village S.S.D.r.l. G. Shulman: Consultant; Current; Novo Nordisk A/S. Research Support; Current; Novo Nordisk A/S. Other - collaboration; Current; Ionis Pharmaceuticals. Advisory Panel; Current; ESPERION Therapeutics, Inc. Research Support; Current; Novo Nordisk Foundation. Advisory Panel; Current; Orsobio. Research Support; Current; Orsobio. Advisory Panel; Current; Village S.S.D. S. Kahl: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. Funding Anna Wunderlich und Ernst Jühling Award, Deutsche Diabetes Gesellschaft (DDG, Allgemeine Projektförderung), European Association for the Study of Diabetes (EASD Rising Star Fellowship)

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