Improving Metabolic Health Through Precision Dietetics in Mice

Barrington, William; Wulfridge, Phillip; Wells, Ann; Rojas, Carolina Mantilla; Howe, Selene; Perry, Amie; Hua, Kunjie; Pellizzon, Michael; Hansen, Kasper D.; Voy, Brynn H.; Bennett, Brian J.; Pomp, Daniel; Feinberg, Andrew P.; Threadgill, David W.

doi:10.1534/genetics.117.300536

Cited by 55 publications

(81 citation statements)

References 101 publications

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“…A recent study by Threadgill and colleagues compared the metabolic effects of the Western-style diet to a control diet, and three additional diets (Mediterranean, Japanese, and Maasai/ketogenic) in four mouse strains; A/J, C57BL/6J, FVB/NJ and NOD/ShiltJ (BARRINGTON et al 2018). The Western-style diet, compared to a control diet, had detrimental health effects, such as increased body fat, LDL-cholesterol and liver triglycerides in all strains, but the effect size varied across stains.…”

Section: Introductionmentioning

confidence: 99%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

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The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse with those found in human populations and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.4

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Section: Introductionmentioning

confidence: 99%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

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“…Relative to an ad libitum diet-a condition far from the natural pattern of food consumption-caloric restriction and intermittent fasting improve lifespan and health (reviewed by Heilbronn and Ravussin, 2003;Liang et al, 2018;Speakman et al, 2016). Effects are not entirely dependent on patterns of caloric intake, but depend on dietary macro-and micronutrient composition, the amount of time spent in different metabolic states, age of onset, sex, and perhaps of most importance to us, differences in genotype (Vaughan et al, 2018) and gene-by-diet interactions (Barrington et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Gene-by-environmental modulation of longevity and weight gain in the murine BXD family

Roy

Sleiman

Jha

et al. 2019

Preprint

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Diet and environmental factors profoundly modulate lifespan. We measured longevity as a function of diet, and weight gain across a large genetically diverse BXD cohort which segregates for over 6 million variants, making it ideal for the analysis of gene-by-diet interactions that modulate lifespan. We followed 1348 females from parental strains, C57BL/6J and DBA/2J, and 76 BXD progeny strains on a standard low fat diet (CD, 18% calories from fat) or a widely used high fat diet (HFD, 60% calories from fat) across their natural life span. A diet rich in saturated fats shortens lifespan by an average of 85 days (HFD 605 ± 6, n = 685; CD 690 ± 8, n = 663), roughly equivalent to a 7-year decrease in humans. This diet is associated with an average two-fold higher age-adjusted risk of death compared to CD. Individual strains show remarkably wide variation in responses to diet, ranging from -54% on HFD in BXD65 to +37% on HFD in BXD8.Baseline weight and early weight gain on HFD associates negatively with longevity, with a gram increase causing lifespan to decrease by 4 days. By 500 days of age, BXDs on HFD gained 4X more weight than those on CD. However, strain-specific variation in the change in body weight does not significantly correlate with strain-specific life span. Major morbidities appear to be influenced by diet, with cases on HFD showing increased prevalence and severity of cardiovascular disease and lesions. Overall, we find that diet significantly impacts longevity even after adjusting for weight gain.

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“…122,123 Characterization sufficient for the detection of such minor components, known or unknown, is therefore critical for quality control and for monitoring batch-to-batch variation and stability. 17,22,114,125 3.2 | Chemical and metabolic factors ADME is a multistep, dynamic biological process that may be modified by product characteristics as well as by host characteristics 115,[126][127][128][129] including physiology and behavior. 14,124 Descriptions of approaches to NP selection and characterization have been published recently.…”

Section: Np Specifications and Integritymentioning

confidence: 99%

Improving natural product research translation: From source to clinical trial

et al. 2019

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While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a Septe mber, 2018 trans disci plina ry workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research. K E Y W O R D S clinical predictive validity, dietary supplements, model systems, rigor and replicability, value of information | 43 SORKIN et al.still provide invaluable guidance, the results of such trials are often met with concerns that different design choiceswhether of product, dose, timing, participant eligibility criteria, outcomes, etc.-might have yielded a substantially different result. Each interventional trial represents a substantial investment, with well-powered Phase III CTs typically consuming more than $10 million and many person-years. 9,10 Additionally, as time and funds are limited, and participant pools may also be constrained, a decision to invest in a CT often precludes pursuing other research questions, 11 which may provide more useful public health-relevant knowledge than an RCT with an insufficient evidence base.

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Improving Metabolic Health Through Precision Dietetics in Mice

Abstract: Barrington et al. examined the effect of four human diets (American, Mediterranean, Japanese, and Maasai/ketogenic) on metabolic health across four mouse...

Cited by 55 publications

References 101 publications

Genetic Drivers of Pancreatic Islet Function

Genetic Drivers of Pancreatic Islet Function

Gene-by-environmental modulation of longevity and weight gain in the murine BXD family

Improving natural product research translation: From source to clinical trial

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