Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring.

Paternal diet can influence the phenotype of the next generation, yet, the dietary components inducing specific responses in the offspring are not identified. Here, we use the Nutritional Geometry Framework to determine the effects of pre-conception paternal dietary macronutrient balance on offspring metabolic and behavioral traits in mice. Ten isocaloric diets varying in the relative proportion of protein, fats, and carbohydrates are fed to male mice prior to mating. Dams and offspring are fed standard chow and never exposed to treatment diets. Body fat in female offspring is positively associated with the paternal consumption of fat, while in male offspring, an anxiety-like phenotype is associated to paternal diets low in protein and high in carbohydrates. Our study uncovers that the nature and the magnitude of paternal effects are driven by interactions between macronutrient balance and energy intake and are not solely the result of over- or undernutrition.

The effects of paternal dietary fat versus sugar on offspring body composition and anxiety-related behavior.

Increasing evidence suggests that the pre-conception parental environment has long-term consequences for offspring health and disease susceptibility. Though much of the work in this field concentrates on maternal influences, there is growing understanding that fathers also play a significant role in affecting offspring phenotypes. In this study, we investigate effects of altering the proportion of dietary fats and carbohydrates on paternal and offspring body composition and anxiety-related behavior in C57Bl/6-JArc mice. We show that in an isocaloric context, greater dietary fat increased body fat and reduced anxiety-like behavior of studs, whereas increased dietary sucrose had no significant effect. These dietary effects were not reflected in offspring traits, rather, we found sex-specific effects that differed between offspring body composition and behavioral traits. This finding is consistent with past paternal effect studies, where transgenerational effects have been shown to be more prominent in one sex over the other. Here, male offspring of fathers fed high-fat diets were heavier at 10 weeks of age due to increased lean body mass, whereas paternal diet had no significant effect on female offspring body fat or lean mass. In contrast, paternal dietary sugar appeared to have the strongest effects on male offspring behavior, with male offspring of high-sucrose fathers spending less time in the closed arms of the elevated plus maze. Both high-fat and high-sugar paternal diets were found to reduce anxiety-like behavior of female offspring, although this effect was only evident when offspring were fed a control diet. This study provides new understanding of the ways in which diet can shape the behavior of fathers and their offspring and contribute to the development of dietary guidelines to improve obesity and mental health conditions, such as anxiety.

Maternal macronutrient intake effects on offspring macronutrient targets and metabolism.

OBJECTIVE: Exposure in utero to maternal diet can program offspring health and susceptibility to disease. Using C57BL6/JArc mice, we investigated how maternal dietary protein to carbohydrate balance influences male and female offspring appetite and metabolic health. METHODS: Dams were placed on either a low-protein (LP) or high-protein (HP) diet. Male and female offspring were placed on a food choice experiment post weaning and were then constrained to either a standard diet or Western diet. Food intake, body weight, and composition were measured, and various metabolic tests were performed at different timepoints. RESULTS: Offspring from mothers fed HP diets selected a higher protein intake and had increased body weight in early life relative to offspring from LP diet-fed dams. As predicted by protein leverage theory, higher protein intake targets led to increased food intake when offspring were placed on no-choice diets, resulting in greater body weight and fat mass. The combination of an HP maternal diet and a Western diet further exacerbated this obesity phenotype and led to long-term consequences for body composition and metabolism. CONCLUSIONS: This work could help explain the association between elevated protein intake in humans during early life and increased risk of obesity in childhood and later life.

Toward reconciling the roles of FGF21 in protein appetite, sweet preference, and energy expenditure.

Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction independently of an animal's energy status, exerts profound effects on feeding behavior and metabolism. Here, we demonstrate that considering the nutritional contexts within which FGF21 is elevated can help reconcile current controversies over its roles in mediating macronutrient preference, food intake, and energy expenditure. We show that FGF21 is primarily a driver of increased protein intake in mice and that the effect of FGF21 on sweet preference depends on the carbohydrate balance of the animal. Under no-choice feeding, FGF21 infusion either increased or decreased energy expenditure depending on whether the animal was fed a high- or low-energy diet, respectively. We show that while the role of FGF21 in mediating feeding behavior is complex, its role in promoting protein appetite is robust and that the effects on sweet preference and energy expenditure are macronutrient-state-dependent effects of FGF21.

Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health.

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.

Sex-specific metabolic responses to 6 hours of fasting during the active phase in young mice.

KEY POINTS: Night time/active phase food restriction for 6 h impaired glucose intolerance in young male and female mice. Females displayed increased capacity for lipogenesis and triglyceride storage in response to a short daily fast. Females had lower fasting insulin levels and an increased potential for utilizing fat for energy through ß-oxidation compared to males. The need for the inclusion of both sexes, and the treatment of sex as an independent variable, is emphasized within the context of this fasting regime. ABSTRACT: There is growing interest in understanding the mechanistic significance and benefits of fasting physiology in combating obesity. Increasing the fasting phase of a normal day can promote restoration and repair mechanisms that occur during the post-absorptive period. Most studies exploring the effect of restricting food access on mitigating obesity have done so with a large bias towards the use of male mice. Here, we disentangle the roles of sex, food intake and food withdrawal in the response to a short-term daily fasting intervention, in which food was removed for 6 h in the dark/active phase of young, 8-week-old mice. We showed that the removal of food during the dark phase impaired glucose tolerance in males and females, possibly due to the circadian disruption induced by this feeding protocol. Although both sexes demonstrated similar patterns of food intake, body composition and various metabolic markers, there were clear sex differences in the magnitude and extent of these responses. While females displayed enhanced capacity for lipogenesis and triglyceride storage, they also had low fasting insulin levels and an increased potential for utilizing available energy sources such as fat for energy through ß-oxidation. Our results highlight the intrinsic biological and metabolic disparities between male and female mice, emphasizing the growing need for the inclusion of both sexes in scientific research. Furthermore, our results illustrate sex-specific metabolic pathways that regulate lipogenesis, obesity and overall metabolic health.