Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic disorders

AbstractObesity is a growing societal scourge responsible for approximately 4 million deaths worldwide. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal western diet feeding for five consecutive generations in mice induces a gradual enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males develop a “healthy” overweight phenotype that is not reversed after 4 subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

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Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice

eLife ◽

10.7554/elife.61736 ◽

2021 ◽

Vol 10 ◽

Author(s):

Georges Raad ◽

Fabrizio Serra ◽

Luc Martin ◽

Marie-Alix Derieppe ◽

Jerome GILLERON ◽

...

Keyword(s):

Metabolic Diseases ◽

Epigenetic Inheritance ◽

Metabolic Health ◽

Western Diet ◽

Chow Diet ◽

Normal Glucose ◽

Obesogenic Diet ◽

Unbalanced Diet ◽

Generation Male

Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for 4 subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

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Chromatin Modifiers SET-25 and SET-32 Are Required for Establishment but Not Long-Term Maintenance of Transgenerational Epigenetic Inheritance

Cell Reports ◽

10.1016/j.celrep.2018.10.085 ◽

2018 ◽

Vol 25 (8) ◽

pp. 2259-2272.e5 ◽

Cited By ~ 23

Author(s):

Rachel M. Woodhouse ◽

Gabriele Buchmann ◽

Matthew Hoe ◽

Dylan J. Harney ◽

Jason K.K. Low ◽

...

Keyword(s):

Epigenetic Inheritance ◽

Transgenerational Epigenetic Inheritance ◽

Term Maintenance ◽

Chromatin Modifiers

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Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00539.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. G956-G967 ◽

Cited By ~ 84

Author(s):

Joel R. Garbow ◽

Jason M. Doherty ◽

Rebecca C. Schugar ◽

Sarah Travers ◽

Mary L. Weber ◽

...

Keyword(s):

Ketogenic Diet ◽

Western Diet ◽

Whole Body ◽

Resonance Spectroscopy ◽

Chow Diet ◽

High Fat ◽

Low Protein ◽

Low Carbohydrate ◽

Term Administration

Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.

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Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health

Biology ◽

10.3390/biology10040336 ◽

2021 ◽

Vol 10 (4) ◽

pp. 336

Author(s):

Jibran A. Wali ◽

Samantha M. Solon-Biet ◽

Therese Freire ◽

Amanda E. Brandon

Keyword(s):

Insulin Resistance ◽

Dietary Intervention ◽

Metabolic Diseases ◽

Metabolic Health ◽

Nutritional Science ◽

Prevalence Of Obesity ◽

Modifiable Factor

Obesity caused by the overconsumption of calories has increased to epidemic proportions. Insulin resistance is often associated with an increased adiposity and is a precipitating factor in the development of cardiovascular disease, type 2 diabetes, and altered metabolic health. Of the various factors contributing to metabolic impairments, nutrition is the major modifiable factor that can be targeted to counter the rising prevalence of obesity and metabolic diseases. However, the macronutrient composition of a nutritionally balanced “healthy diet” are unclear, and so far, no tested dietary intervention has been successful in achieving long-term compliance and reductions in body weight and associated beneficial health outcomes. In the current review, we briefly describe the role of the three major macronutrients, carbohydrates, fats, and proteins, and their role in metabolic health, and provide mechanistic insights. We also discuss how an integrated multi-dimensional approach to nutritional science could help in reconciling apparently conflicting findings.

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The chromatin modifiers SET-25 and SET-32 are required for initiation but not long-term maintenance of transgenerational epigenetic inheritance

10.1101/255646 ◽

2018 ◽

Cited By ~ 1

Author(s):

Rachel Woodhouse ◽

Gabrielle Buchmann ◽

Matthew Hoe ◽

Dylan Harney ◽

Mark Larance ◽

...

Keyword(s):

Small Rna ◽

Epigenetic Inheritance ◽

Small Rna Sequencing ◽

Chromatin Modifications ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

Secondary Sirnas ◽

Rna Pathways ◽

Term Maintenance

SummarySome epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNA interference phenotypes in Caenorhabditis elegans provides an excellent model to study this phenomenon, and whilst studies have implicated both chromatin modifications and small RNA pathways in heritable silencing their relative contributions remain unclear. Here we demonstrate that the histone methyltransferases SET-25 and SET-32 are required for the establishment of a transgenerational silencing signal but not for long-term maintenance of this signal between subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete.

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