Genetic, metabolic, and molecular insights into the diverse outcomes of diet-induced obesity in mice

Overweight and obesity are increasingly common public health issues worldwide, leading to a wide range of diseases from metabolic syndrome to steatohepatitis and cardiovascular diseases. While the increase in the prevalence of obesity is partly attributable to changes in lifestyle (i.e. increased sedentarity and changes in eating behaviour), the metabolic and clinical impacts of these obesogenic conditions varies between sexes and genetic backgrounds. The conception of personalised treatments of obesity and its complications require a thorough understanding of the diversity of responses to conditions such as high-fat diet intake. By analysing nine genetically diverse mouse strains, we show that much like humans, mice respond to high-fat diet in a genetic- and sex-dependent manner. Physiological and molecular responses to high-fat diet are associated with expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function may explain part of the diversity of physiological responses. By exploring the complex interactions between genetics and metabolic phenotypes via gene expression and molecular traits, we shed light on the importance of genetic background and sex in determining metabolic outcomes. In addition to providing the community with an extensive resource for optimizing future experiments, our work serves as an exemplary design for more generalizable translational studies.

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Maternal high-fat diet programs white and brown adipose tissue lipidome and transcriptome in offspring in a sex- and tissue-dependent manner in mice

International Journal of Obesity ◽

10.1038/s41366-021-01060-5 ◽

2022 ◽

Author(s):

Christina Savva ◽

Luisa A. Helguero ◽

Marcela González-Granillo ◽

Tânia Melo ◽

Daniela Couto ◽

...

Keyword(s):

High Fat Diet ◽

Metabolic Profile ◽

Maternal Diet ◽

Overweight And Obesity ◽

Male Offspring ◽

Metabolic Adaptation ◽

Dependent Manner ◽

High Fat ◽

The Metabolic Syndrome ◽

Metabolic Complication

Abstract Objective The prevalence of overweight and obesity among children has drastically increased during the last decades and maternal obesity has been demonstrated as one of the ultimate factors. Nutrition-stimulated transgenerational regulation of key metabolic genes is fundamental to the developmental origins of the metabolic syndrome. Fetal nutrition may differently influence female and male offspring. Methods Mice dam were fed either a control diet or a high-fat diet (HFD) for 6-week prior mating and continued their respective diet during gestation and lactation. At weaning, female and male offspring were fed the HFD until sacrifice. White (WAT) and brown (BAT) adipose tissues were investigated in vivo by nuclear magnetic resonance at two different timepoints in life (midterm and endterm) and tissues were collected at endterm for lipidomic analysis and RNA sequencing. We explored the sex-dependent metabolic adaptation and gene programming changes by maternal HFD in visceral AT (VAT), subcutaneous AT (SAT) and BAT of offspring. Results We show that the triglyceride profile varies between adipose depots, sexes and maternal diet. In female offspring, maternal HFD remodels the triglycerides profile in SAT and BAT, and increases thermogenesis and cell differentiation in BAT, which may prevent metabolic complication later in life. Male offspring exhibit whitening of BAT and hyperplasia in VAT when born from high-fat mothers, with impaired metabolic profile. Maternal HFD differentially programs gene expression in WAT and BAT of female and male offspring. Conclusion Maternal HFD modulates metabolic profile in offspring in a sex-dependent manner. A sex- and maternal diet-dependent gene programming exists in VAT, SAT, and BAT which may be key player in the sexual dimorphism in the metabolic adaptation later in life.

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Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

Journal of Endocrinology ◽

10.1530/joe-18-0289 ◽

2018 ◽

Vol 239 (3) ◽

pp. 377-388 ◽

Cited By ~ 1

Author(s):

Rumana Yasmeen ◽

Qiwen Shen ◽

Aejin Lee ◽

Jacob H Leung ◽

Devan Kowdley ◽

...

Keyword(s):

Energy Expenditure ◽

High Fat Diet ◽

Ex Vivo ◽

Mapk Pathway ◽

Treated Group ◽

Dependent Manner ◽

High Fat ◽

Fat Depots ◽

Expression Of Genes

Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

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Mitochondrial Function and Protein Expression in C5L2KO Mouse Skeletal Muscle after 10 Weeks of High-Fat Diet Intake

10.1210/endo-meetings.2011.part4.p2.p3-441 ◽

2011 ◽

pp. P3-441-P3-441

Author(s):

Christian Roy ◽

Sabina Paglialunga ◽

Joris Hoeks ◽

Katherine Cianflone ◽

Patrick Schrauwen

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Mitochondrial Function ◽

High Fat Diet ◽

High Fat ◽

Mouse Skeletal Muscle ◽

Diet Intake

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Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00044.2010 ◽

2010 ◽

Vol 42A (4) ◽

pp. 228-234 ◽

Cited By ~ 3

Author(s):

Renhua H. Li ◽

Gary A. Churchill

Keyword(s):

High Fat Diet ◽

Genetic Factors ◽

Inbred Mouse ◽

Plasma Concentrations ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Mouse Strains ◽

High Fat ◽

Expression Of Genes ◽

Genetic Buffering

Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J × DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain.

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Palatable high-fat diet intake influences mnemonic and emotional aspects in female rats in an estrous cycle-dependent manner

Metabolic Brain Disease ◽

10.1007/s11011-021-00812-6 ◽

2021 ◽

Author(s):

Sara Pereira Silva ◽

José Ivo Araújo Beserra-Filho ◽

Melina Chiemi Kubota ◽

Gabriela Nascimento Cardoso ◽

Francisca Rayanne Silva Freitas ◽

...

Keyword(s):

Estrous Cycle ◽

High Fat Diet ◽

Female Rats ◽

Dependent Manner ◽

High Fat ◽

Emotional Aspects ◽

Diet Intake ◽

Cycle Dependent

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High fat diet and pressure overload: Relation of mitochondrial function and contractile function

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0034-1367122 ◽

2014 ◽

Vol 62 (S 01) ◽

Author(s):

A. Schrepper ◽

M. Schwarzer ◽

S. Freiberger ◽

T. Doenst

Keyword(s):

Mitochondrial Function ◽

High Fat Diet ◽

Contractile Function ◽

Pressure Overload ◽

High Fat

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Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus

Scientific Reports ◽

10.1038/s41598-021-95353-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Laura K. Cole ◽

Genevieve C. Sparagna ◽

Marilyne Vandel ◽

Bo Xiang ◽

Vernon W. Dolinsky ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Mitochondrial Function ◽

High Fat Diet ◽

Fatty Acid Uptake ◽

Isoquinoline Alkaloid ◽

Acid Uptake ◽

High Fat ◽

Low Fat

AbstractBerberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. We examined the role of the mitochondrial phospholipid cardiolipin (CL) in mediating this cardiac improvement. C57BL/6 female mice were fed either a Lean-inducing low-fat diet or a GDM-inducing high-fat diet for 6 weeks prior to breeding. Lean and GDM-exposed male offspring were randomly assigned a low-fat, high-fat, or high-fat diet containing BBR at weaning for 12 weeks. The content of CL was elevated in the heart of GDM offspring fed a high fat diet containing BBR. The increase in total cardiac CL was due to significant increases in the most abundant and functionally important CL species, tetralinoleoyl-CL and this correlated with an increase in the expression of the CL remodeling enzyme tafazzin. Additionally, BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Thus, dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL.

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PHARMACOLOGICAL SCREENING OF ANTI-OBESITY POTENTIAL OF ACORUS CALAMUS LINN. IN HIGH FAT CAFETERIA DIET FED OBESE RATS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i4.16893 ◽

2017 ◽

Vol 10 (4) ◽

pp. 384 ◽

Cited By ~ 2

Author(s):

Athesh K ◽

Joshi G

Keyword(s):

Body Weight ◽

High Fat Diet ◽

Serum Glucose ◽

In Vivo Studies ◽

Acorus Calamus ◽

Dependent Manner ◽

Fat Pad ◽

High Fat ◽

Dose Levels ◽

Dose Dependent

Objective: To study the anti-obesity potential of aqueous rhizome extract of Acoruscalamus Linn. (AREAC)in high fat diet fed obese rats.Methods: Adult strain male Wistar rats used in this study were fed with High Fat Diet (HFD) for 60 days. For the treatment groups,AREAC was administered in a dose levels of100, 200 and 300 mg/kgbw, orally once a day along with HFD. Rats fed with normal pellet chow were served as normal control. The effect of AREAC on physical parameterssuch as body weight, organ weight, fat pad weights and various biochemical parameterslike serum glucose, insulin, leptin,lipid profile, liver markers, kidney markers and oxidative stress markers were analysed.In-vitro pancreatic lipase inhibition assay of AREAC was also studied.Results: Data of in-vivo studies revealedsignificant (p<0.05) reduction in percentage body weight gain, organ weights, fat pad weights and levels of serum glucose, insulin and leptin after treatment with AREAC in a dose dependent manner. Also, administration of AREAC significantly inhibited the increases in the concentrations of triglycerides, total cholesterol, LDL-cholesterol, VLDL-cholesterol, free-fatty acid and phospholipids in a dose dependent manner whereas, the level of HDL-cholesterol was found to be elevated on treatment. Moreover, on treatment with test drug,the elevated levels of serum liver and kidney markerssuch as AST, ALT, ALP, urea, creatinine were also brought back to near normalcy. Antioxidant status was found to be enhanced in liver tissues after treatment.In-vitro studies showed significant inhibition in the activity of pancreatic lipaseby AREAC.Conclusion: The data of the results obtained clearly depicted that AREAC was found to have pronounced anti-obesity activity particularly at the dose levels of 300 mg/kg bw.Key Words: Obesity, High Fat Diet, Leptin, AcoruscalamusLinn., Orlistat.

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High Mortality with Severe Dystrophic Cardiac Calcinosis in C3H/OUJ Mice Fed High Fat Purified Diets

Veterinary Pathology ◽

10.1177/030098588802500202 ◽

1988 ◽

Vol 25 (2) ◽

pp. 113-118 ◽

Cited By ~ 16

Author(s):

J. I. Everitt ◽

L. M. Olson ◽

J. B. Mangum ◽

W. J. Visek

Keyword(s):

High Fat Diet ◽

Inflammatory Cell ◽

Mouse Strains ◽

Cardiovascular Collapse ◽

Pathological Changes ◽

High Fat ◽

Low Fat Diet ◽

Myocardial Degeneration ◽

Lactating Females ◽

Hydrogenated Soybean Oil

Severe degenerative myocardial disease occurred in female C3H/OUJ mice fed purified diets for 36 weeks; the diet contained 5% or 20% fat as non-hydrogenated soybean oil. Deaths of lactating females of this group (17/35 high fat diet and 7/35 low fat diet animals) were due to sudden cardiovascular collapse. Cardiomegaly with marked atrial and ventricular myocardial mineralization was seen at necropsy. Histologically. the random, myopathic foci were characterized by severe myocardial degeneration, mineralization, and fibrosis. Mural thrombosis, pulmonary arteriosclerosis, and mild myocardial inflammatory cell infiltrates were also present. Pathological changes were similar to those of dystrophic cardiac calcinosis, an incidental necropsy finding in certain mouse strains.

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