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

Abstract

20Obesity is a growing societal scourge responsible for approximately 4 million deaths 21 worldwide. Recent studies have uncovered that paternal excessive weight induced by an 22 unbalanced diet affects the metabolic health of offspring. These reports mainly employed 23 single-generation male exposure. However, the consequences of multigenerational 24 unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we 25 show that maintaining paternal western diet feeding for five consecutive generations in mice 26 induces a gradual enhancement in fat mass and related metabolic diseases over generations. 27Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males 28 develop a "healthy" overweight phenotype that is not reversed after 4 subsequent generations. 29Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm 30 RNAs are sufficient for establishment but not for long-term maintenance of epigenetic 31 inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation 32 induced by successive paternal western-diet-fed generations may contribute to the worldwide 33 epidemic of metabolic diseases. 35 Introduction 36Nongenetic inheritance of newly acquired phenotypes is a new concept in biology whereby 37 changes induced by specific environmental cues in parents (mothers and/or fathers) can be 38 transmitted to the next generation [1][2][3]. This process is evolutionarily conserved and has been 39 described from worms to humans [4][5][6][7]. The fact that environmental cues have the potential to 40 modify the molecular hereditary information carried by the spermatozoa demonstrates that the 41 environmentally induced epigenetic modifications [8][8] are not erased through the epigenetic 42 reprogramming process, causing them to be inherited by the next generations [9, 10]. Although 43 the role of epigenetic modifications such as DNA methylation [9, 11, 12] and chromatin 44 modification [13, 14] cannot be excluded in this process, independent experimental data 45 strongly evoke the central role of sperm RNA as a vector of paternal intergenerational 46 epigenetic inheritance of, at least, environmentally induced metabolic pathologies [1, 3, 15].47 Unlike genetic inheritance, environmentally induced epigenetic alterations are reversible, 48 enabling the loss of previously acquired characteristics [16]. Although environmental changes 49 might persist over several generations, most reports have been based on the maintenance of 50 paternal environmental cues for just one generation [17]. This is particularly true for certain 51 lifestyle habits, such as eating high-fat and high-sugar junk food, also called a Western diet 52 (WD). Thus, although people around the world may face multigenerational unbalanced 53 nutrition, there have been limited studies on its effects on the metabolic health of the progeny. 54Herein, we studied the impact of the paternal maintenance of an unhealthy WD for multiple 55 generations on the me...