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High Fat Diet Metabolism and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 January 2026) | Viewed by 12969

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Special Issue Editors

Dr. Miguel Walter Fornés

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Guest Editor

Institute of Histology and Embriology from Mendoza—IHEM, CONICET Mendoza, Universidad Nacional de Cuyo, Mendoza, Argentina
Interests: high-fat diet; Metabolism; Cholesterol
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Luís Fernando Barbisan

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Guest Editor

Department of Cellular and Molecular Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, Brazil
Interests: MASLD models; food additives; functional foods; oxidative and antioxidant response; prevention
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The term “diet” traces its roots to the Latin “diaeta” and the Greek “δίαιτα”, inherently conveying the broader notion of “lifestyle”, a comprehensive concept extending far beyond food intake. It encapsulates various facets of one's existence, including work routines, physical activity, age, and gender, all shaping an individual's health.

Fat diet refers surreptitiously to the typical intake of Western countries. However, in modern usage, the term has become closely linked to food consumption, particularly the increase in fats in diets across Western countries, a trend now spreading worldwide.

For these simple reasons, among many others, research with “high-fat diets” or other diets must include the specific daily consumption of the compounds present in the foods used, as well as ages, sex, and other variables that affect metabolism and generate related pathologies. These variables often have profound implications on cellular and molecular biology, underpinning the intricate interplay between diets and health. Interestingly, all organs and systems respond by adapting to the internal conditions that generate these diets, forming the basis of known pathologies.

This Special Issue will explore the intricate relationship between high-fat diets and health. We invite researchers to submit their work examining how these diets affect metabolism, from cell to molecular biology, lead to diverse pathologies, and impact various organs and systems—from the reproductive to the lungs. We are only beginning to unravel the far-reaching effects of high-fat diets, and your contributions can help deepen our understanding of this global health challenge.

Dr. Miguel Walter Fornés
Prof. Dr. Luís Fernando Barbisan
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

diet
fat
high-fat diets
obesity
NAFLD
metabolism
reproductive system
lungs
pathology

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Published Papers (9 papers)

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Research

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21 pages, 1541 KB

Open AccessArticle

Extracellular Vesicle from Chlorella vulgaris Alleviates Hepatic Fibrosis in a Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease Through Modulation of Inflammatory Signaling

by Hinata Harada, Yusuke Ohsaki, Afifah Zahra Agista, Hsin-Jung Ho, Takuo Hirose, Kotaro Yamada, Mutsumi Furukawa, Tomonori Nochi, Wan-Chun Chiu, Ya-Ling Chen, Chiu-Li Yeh, Suh-Ching Yang, Takefumi Mori and Hitoshi Shirakawa

Int. J. Mol. Sci. 2026, 27(9), 3735; https://doi.org/10.3390/ijms27093735 - 22 Apr 2026

Viewed by 193

Abstract

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a major chronic liver disorder that progresses through inflammation and fibrosis to cirrhosis, yet no effective pharmacological therapy is available. Extracellular vesicles (EVs), which are key mediators of intercellular communication, have recently been reported to exert preventative and therapeutic effects in disease models. This study evaluated the oral efficacy of EVs derived from the microalga Chlorella vulgaris (CEVs) in an MASLD mouse model. Male C57BL/6J mice were assigned to a control group (normal diet), an MASLD group (choline- and methionine-deficient high-fat diet; CDHF), or CEV group (CDHF + CEVs). Twelve-week CEV administration did not alter the CDHF-induced reduction in circulating lipid levels or produce an increase in hepatic lipid content. However, CEV treatment significantly suppressed CDHF-induced fibrosis with collagen accumulation and reduced the mRNA expression of fibrosis-related genes, including Col1a1, Acta2, Mmp2, and Timp1. CEVs also significantly downregulated the expression of macrophage-derived inflammatory mediators—Ccl2, Ccr2, Il6 and Il1b—and reduced lobular inflammatory foci. These findings suggest that CEVs attenuate hepatic fibrosis by modulating early inflammation associated with steatosis and inhibiting hepatic stellate cell activation. This study supports the potential of CEVs as a novel oral intervention for slowing MASLD progression. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

33 pages, 9058 KB

Open AccessArticle

Sex Differences in Dietary-Induced Liver Steatosis and Insulin Receptor-Related Signaling in Aged Mice Lacking Serotonin Transporter

by Raymond Cespuglio, Konstantin Zabegalov, Johannes P. M. de Munter, Anna Gorlova, Kirill Chaprov, Daria Rogacheva, Sholpan Askarova, Angelika Schmitt-Böhrer, Aleksei Deykin, Klaus-Peter Lesch and Tatyana Strekalova

Int. J. Mol. Sci. 2026, 27(6), 2836; https://doi.org/10.3390/ijms27062836 - 20 Mar 2026

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Abstract

Sex differences remain largely underexplored in metabolic disorders, particularly in the context of genetic predisposition to type 2 diabetes, the impact of aging, and environmental factors such as exposure to high-caloric diets. Previous studies using serotonin transporter (SERT)-knockout (SERT-KO) mice, which recapitulate metabolic conditions related to the lowered function of this transporter in humans, revealed an aggravated negative response of these mutants to housing on a high-fat/sugar ‘Western diet’ (WD). However, the role of sex in SERT-KO mice has not yet been studied. Available human and animal data suggest the differential regulation of insulin receptor-mediated signaling in males and females, which can be altered with aging. This study aimed to compare fat accumulation, blood biochemical changes, glucose tolerance, and insulin receptor (IR)-related signaling in the liver and various brain structures of 12-month-old male and female SERT-KO mice fed WD for 21 days. Relative to the dietary-unchallenged group and their wild-type (WT) littermates, WD-fed mutants of both sexes displayed markedly increased fat accumulation and impaired glucose and insulin tolerance. Body mass increase was more prominent in females than in males. The two sexes revealed a similar suppression of the gene expression of isoforms A and B of IR but distinct expression of IR-related factors. IR-related genes such as Cd36, Enpp, Ptpn1, Cyp4a14, Acsl1, and Pten showed differential expression between male and female SERT-KO mice fed WD. Several differences in gene expression were also found between the WT groups of the two sexes. Overall, the manifestations of hepatic steatosis, insulin resistance, and glucose tolerance were similar between the age groups of animals, whereas the gene expression of IR-related regulation differed between the groups. We conclude that aging and genetic absence of the serotonin transporter likely override sex differences in the end effects of WD challenge, while molecular mechanisms of adaptation of IR-mediated signaling are distinct between male and female SERT-KO mice fed WD. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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19 pages, 5088 KB

Open AccessArticle

Ammonium Hydroxide Enhancement of Dietary Protein in High-Fat Diets Modulates Liver Metabolism Signaling in a Sex- and Age-Dependent Manner in C3H/HeJ Mice

by Benjamin R. Barr, Indhu Subramaniyan, Li Li, Danielle E. Levitt and Lauren S. Gollahon

Int. J. Mol. Sci. 2026, 27(1), 403; https://doi.org/10.3390/ijms27010403 - 30 Dec 2025

Cited by 2 | Viewed by 669

Abstract

(1) Lifestyle changes to modify unhealthy dietary patterns with the goal of preventing MASLD have proven challenging. Here, dietary proteins and their modification with ammonium hydroxide enhancement (AHE) provide molecular evidence that this novel approach may attenuate the development of MASLD without undue dietary adjustments, potentially bypassing non-compliance. (2) High-fat diets containing dietary beef (HFB) or casein (HFC) + AHE (HFBN and HFCN, respectively) were fed to 256 C3H/HeJ female and male mice long term. At 6, 12, or 18 months, hepatic samples were analyzed with targeted metabolomics (glucose, lactate, alanine, glutamine, carnitine) and Western analysis (β-catenin, glutamine synthetase, CYP3A4). RNA sequencing was performed on samples collected at 18 months (n = 3; male HFC n = 2). (3) Metabolomics results showed that at 18 months, hepatic glutamine was greater in HFBN versus HFCN in females, whereas in males, hepatic glutamine, glucose and lactate were lower in HFBN versus HFCN. Additionally, diets with AHE decreased β-catenin and CYP3A4 protein expression in males. Ingenuity pathway analysis (IPA) of RNA-seq data predicted that HFBN activates PPARα signaling in the liver in both sexes compared to HFCN. Inflammatory activity showed predicted activation for females in the HFBN:HFCN comparison. In males, the inflammatory pathway molecular mechanisms of cancer was predicted as deactivated in HFBN:HFCN. (4) Dietary protein source impacts outcomes, and these outcomes improved with AHE. The HFBN diet improves signaling associated with lipid utilization for females and males, and improved inflammatory signaling for males compared with HFCN. Further exploration of AHE as a dietary intervention in high-fat diets is warranted. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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20 pages, 1103 KB

Open AccessArticle

High-Fat Diet Alters Behavior and Hippocampal Gene Expression

by Melissa S. Totten, Ava L. Peterson, Derek M. Pierce and Keith M. Erikson

Int. J. Mol. Sci. 2025, 26(18), 9241; https://doi.org/10.3390/ijms26189241 - 22 Sep 2025

Viewed by 2102

Abstract

Consuming a high-fat diet (HFD) has been linked to gene expression alterations and negative behavior changes. The aim of this study was to evaluate the impact of a HFD on behavior and gene expression in the hippocampi of male and female mice from different strains to evaluate sex and genetic differences. C57BL/6J (B6J) and DBA/2J (D2J) mice were randomly assigned to either a control diet containing 10% kcal fat or a HFD containing 60% kcal fat for 16 weeks. Behavior was measured using the open field test for anxiety, nestlet shredding for general welfare, and novel object recognition for memory. Alpha synuclein (αSYN), amyloid precursor protein (APP), and brain-derived neurotrophic factor (BDNF) mRNA expression was assessed. The HFD led to reduced nestlet shredding for male B6J mice exclusively. There was a significant main effect of sex for fecal boli within the B6J strain and higher levels of fecal boli only for HFD male B6Js. No difference in memory was found in either strain. Significant three-way interactions between diet, sex, and strain for mRNA expression of aSYN and APP were found. However, the simple main effect of diet was only significant in the male B6J strain, revealing a 7-fold upregulation of hippocampal αSYN expression and 10-fold upregulation of APP in the HFD group compared to the control diet group. Although there was a significant strain by sex interaction effect for BDNF expression, there was no effect of diet on either strain. Overall, the HFD treatment impacted male B6J mice the greatest. This study demonstrates that biological sex and genetic factors should be considered when examining the impact of diet on behavior and the brain. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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21 pages, 3697 KB

Open AccessArticle

Anti-Obesity Effects of Rosa rugosa Thunb. Flower Bud Extracts on Lipid Metabolism Regulation in 3T3-L1 Adipocytes and Sprague Dawley Rats

by Jung Min Kim, Kyoung Kon Kim, Hye Rim Lee, Jae Cheon Im and Tae Woo Kim

Int. J. Mol. Sci. 2025, 26(14), 6963; https://doi.org/10.3390/ijms26146963 - 20 Jul 2025

Cited by 1 | Viewed by 1504 | Correction

Abstract

In modern society, obesity and its associated complications have emerged as serious public health concerns, primarily stemming from sedentary lifestyles and carbohydrate-rich diets. Due to the severe side effects often associated with pharmacological anti-obesity agents, emerging global efforts focus on preventive strategies, e.g., dietary modifications and weight gain-suppressing functional foods. In this context, plant-derived metabolites are extensively investigated for their beneficial anti-obesity effects. In this study, we evaluated how Rosa rugosa Thunb. flower bud extract affects fat metabolism in 3T3-L1 preadipocyte cells. The extract significantly inhibited adipocyte differentiation and intracellular triglyceride accumulation in 3T3-L1 cells, enhanced lipolysis, suppressed lipogenesis, and promoted energy metabolism in differentiated adipocytes. In vivo, it reduced body and organ weights and fat mass in high-fat diet-induced obese rats, along with marked adipocyte size and hepatic lipid accumulation reductions. In the epididymal adipose tissue, the extract similarly enhanced lipolytic activity, suppressed lipogenic enzyme expression, and stimulated energy expenditure. Taken together, our results demonstrate the potential of R. rugosa Thunb. flower bud extract in reducing fat accumulation through lipid metabolism modulation both in cellular and animal models. Further studies are warranted to identify the active constituents and evaluate the safety and efficacy of the extract in clinical applications. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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27 pages, 7482 KB

Open AccessArticle

Cholesterol and SREBP2 Dynamics During Spermatogenesis Stages in Rabbits: Effects of High-Fat Diet and Protective Role of Extra Virgin Olive Oil

by María Virginia Avena, Abi Karenina Funes, María Ángeles Monclus, Paola Vanina Boarelli, Luis Fernando Barbisan, M. Rosa Bernal-López, Ricardo Gómez-Huelgas, Tania Estefania Saez Lancellotti and Miguel Walter Fornés

Int. J. Mol. Sci. 2025, 26(9), 4062; https://doi.org/10.3390/ijms26094062 - 25 Apr 2025

Cited by 1 | Viewed by 1219

Abstract

High-fat diets (HFDs) have been found to compromise male fertility, with cholesterol dysregulation being a key factor. Sterol regulatory element-binding protein 2 (SREBP2) is a crucial transcription factor that regulates cholesterol biosynthesis and uptake, playing an essential role in maintaining cholesterol homeostasis in the testes. This study investigated the dynamics of SREBP2 and cholesterol levels during rabbit spermatogenesis under HFD conditions. Our findings reveal that SREBP2 expression fluctuates throughout the seminiferous epithelium cycle. However, HFDs induce stage-specific disruptions in cholesterol balance, leading to sperm with increased membrane cholesterol, a reduced sperm count in semen analysis, impaired motility, abnormal morphology, and decreased functionality. In the control group, SREBP2 expression patterns underscored its critical role in normal spermatogenesis. Interestingly, supplementation with extra virgin olive oil (EVOO) reversed the negative effects of HFD, normalizing SREBP2 expression and cholesterol content, which improved sperm quality. These findings emphasize the importance of stage-specific analysis in understanding how dietary fat impacts male fertility and suggest that EVOO may serve as a potential nutritional intervention to protect reproductive health. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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13 pages, 8103 KB

Open AccessArticle

High-Fat Diets Disturb Rat Epididymal Sperm Maturation

by Lorena Ruiz-Valderrama, José Edwin Mendoza-Sánchez, Ernesto Rodríguez-Tobón, Isabel Arrieta-Cruz, Humberto González-Márquez, Pablo Arturo Salame-Méndez, Rosario Tarragó-Castellanos, Edith Cortés-Barberena, Ahiezer Rodríguez-Tobón and Edith Arenas-Ríos

Int. J. Mol. Sci. 2025, 26(5), 1850; https://doi.org/10.3390/ijms26051850 - 21 Feb 2025

Cited by 9 | Viewed by 2181

Abstract

Infertility is increasingly recognized as being closely linked to obesity in humans. The successful production of fertile spermatozoa requires adequate spermatogenesis within the testis and proper spermatozoa maturation through the epididymis. This study aimed to evaluate the impact of body adiposity on male fertility, focusing on sperm parameters, epididymal sperm maturation, and sperm capacitation in Wistar rats. Male rats were randomized into three dietary groups over four weeks: a control group receiving less than 4% lard, regular chow, a 10% lard group, and a 60% lard group. Following dietary interventions, fertility tests were conducted across the groups. The epididymis was dissected into caput, corpus, and cauda regions to assess sperm concentration, vitality capacitation, carbohydrate distribution, tyrosine phosphorylation, and phosphatidylserine levels. Additionally, serum testosterone levels were measured to evaluate hormonal influences on fertility. The rats subjected to high-fat diets leading to overweight and obesity exhibited significant alterations in fertility. These changes were characterized by impaired epididymal sperm maturation, as evidenced by lower testosterone levels, decreased sperm viability, and capacitation. Furthermore, increased adiposity was associated with a lack of asymmetry in the plasma membrane, alteration in carbohydrate distribution, and changes in tyrosine phosphorylation. This study underscores the adverse effects of high-fat diets on male fertility, particularly through mechanisms affecting sperm maturation in the epididymis. The evidence suggests that obesity-induced alterations in sperm parameters and hormonal profiles may contribute to reduced fertility in male rats, which could have implications for understanding similar human processes. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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Review

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26 pages, 1244 KB

Open AccessReview

High-Fat Diet and Metabolic Diseases: A Comparative Analysis of Sex-Dependent Responses and Mechanisms

by Qiaoling Mo, Xinquan Deng, Ziyu Zhou and Lijun Yin

Int. J. Mol. Sci. 2025, 26(10), 4777; https://doi.org/10.3390/ijms26104777 - 16 May 2025

Cited by 6 | Viewed by 2789

Abstract

Sex differences in metabolic disorders and susceptibility to chronic diseases induced by a high-fat diet (HFD) exhibit significant dimorphic characteristics. A long-standing male-centric bias in medical research and healthcare, predominantly focused on male physiological traits, has hindered the precise treatment of metabolic diseases in female patients. A comprehensive understanding of sex differences in metabolic health and their underlying mechanisms is crucial for advancing personalized health promotion and precision medicine. This review systematically elucidates sex-specific manifestations in high-fat diet-associated metabolic disorders: males predominantly develop visceral adiposity, insulin resistance, and dyslipidemia, accompanied by a significantly elevated risk of cardiovascular and metabolic syndromes. Premenopausal females maintain metabolic homeostasis through the estrogen-mediated optimization of glucose and lipid metabolism and oxidative stress buffering mechanisms, whereas postmenopausal-phase females experience dramatic metabolic vulnerability due to z loss of protective barriers. Furthermore, we emphasize multidimensional mechanistic interpretations of metabolic sexual dimorphism from perspectives including sex chromosome complement, sex hormone signaling pathways, epigenetic regulation, gut microbiota composition, and neuroendocrine dimorphism. This work provides critical theoretical foundations for rectifying unisex research paradigms and optimizing sex-specific early warning systems and precision therapeutic strategies for metabolic disorders. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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