Biology subjects

Babygirija, R.

Publications and source records attributed to Babygirija, R..

6 recordsLinked to original sources

bioRxiv2024

Non-canonical Metabolic and Molecular Effects of Calorie Restriction Are Revealed by Varying Temporal Conditions

Calorie restriction (CR) extends lifespan and healthspan in diverse species. However, comparing ad libitum (AL) and CR-fed mice is challenging due to their significantly different feeding patterns. CR-fed mice consume their daily meal in approximately 2 hours, subjecting themselves to a prolonged self-imposed fast each day. To gain deeper insights into the effects of CR, we conducted a comprehensive examination of how AL and CR-fed mice respond to tests performed at various times relative to the completion of their once-daily CR meal. Our findings reveal that many well-known effects of CR, including its impact on insulin sensitivity, result from the specific temporal conditions. CR animals exhibit a divergent response to insulin, and this response varies based on the time elapsed since the CR-fed mice consumed their food. Utilizing an unbiased metabolomics approach, we discovered that the effects of CR on circulating metabolites are heavily dependent upon the time-of-day and feeding regimen. Finally, while it is widely believed that CR functions in part by reducing activity of the kinase mTORC1, our study suggests that the observed differences in mTORC1 activity between AL and CR-fed mice are dependent upon both fasting duration and the specific tissue examined. Furthermore, we find that the metabolic effects of CR are independent of hepatic mTORC1. Our results shed new light on the physiological, metabolic, and molecular effects of a CR diet, and highlight that much of our understanding of the effects of CR are related to when, relative to feeding, we choose to examine the mice.

physiology↗

bioRxiv2023

Dietary restriction of individual amino acids stimulates unique molecular responses in mouse liver

Dietary protein and essential amino acid (EAA) restriction promote favorable metabolic reprogramming, although the extent to which shared or EAA-specific mechanisms facilitate diet-associated phenotypes remains unclear. Here, we compared the physiological and molecular effects of dietary methionine, leucine, or isoleucine depletion (Met-D, Leu-D, and Ile-D) in C57BL/6J mice. Each diet elicited responses not phenocopied by mTORC1 inhibition, including reduced fat mass and hepatic amino acid catabolism. Ile-D yielded additional distinct responses, highlighted by histone H2A/H4 hypoacetylation and maintained hepatic acetyl-CoA levels despite downregulated FA {beta}-oxidation. Multi-Omics Factor Analysis of 14,139 data points objectively affirmed Ile-D phenotypes are distinct from Met-D or Leu-D and identified several metabolic and chromatin features as primary discriminators. Metabolic and epigenetic responses to Ile-D were recapitulated in vitro, suggesting underlying mechanisms represent fundamental cellular properties. Together, these results demonstrate EAAs can stimulate unique phenotypes and highlight distinct molecular mechanisms by which EAAs may inform metabolic health.

biochemistry↗

bioRxiv2023

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

In defiance of the paradigm that calories from all sources are equivalent, we and others have shown that dietary protein is a dominant regulator of healthy aging. The restriction of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan when initiated in young or adult mice. However, many interventions are less efficacious or even deleterious when initiated in aged animals. Here, we investigate the physiological, metabolic, and molecular consequences of consuming a diet with a 67% reduction of all amino acids (Low AA), or of isoleucine alone (Low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diet regimens effectively reduce adiposity and improve glucose tolerance, which were benefits that were not mediated by reduced calorie intake. Both diets improve specific aspects of frailty, slow multiple molecular indicators of aging rate, and rejuvenate the aging heart and liver at the molecular level. These results demonstrate that Low AA and Low Ile diets can drive youthful physiological and molecular signatures, and support the possibility that these dietary interventions could help to promote healthy aging in older adults.

physiology↗

bioRxiv2022

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

physiology↗

bioRxiv2022

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21-/-and wild-type control mice either ad libitum (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

physiology↗

bioRxiv2022

Regulation of metabolic health by dietary histidine in mice

Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and a low protein diet promotes leanness and glycemic control in both rodents and humans. While the effects of a LP diet on glycemic control are mediated by reduced dietary levels of the branched- chain amino acids (BCAAs), we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces weight gain of young, lean male mice, reducing both adipose and lean mass gain, without altering glucose metabolism. Specifically reducing dietary histidine rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity; this normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. We find that the effects of histidine restriction surprisingly does not require the energy balance hormone Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary levels of histidine may be a highly translatable option for the treatment of obesity. Key PointsO_LIProtein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. C_LIO_LIRestriction of specific individual essential amino acids can recapitulate the benefits of PR. C_LIO_LIReduced histidine promotes leanness and increased energy expenditure in mice. C_LIO_LIReduced histidine does not extend the lifespan of mice when begun in mid-life. C_LIO_LIDietary levels of histidine are positively associated with BMI in humans. C_LI

physiology↗