Biology subjects

Aldiss, P.

Publications and source records attributed to Aldiss, P..

4 recordsLinked to original sources

bioRxiv2024

Sucrase isomaltase dysfunction influences dietary sucrose intake and preference

ObjectiveTo characterise the role of Sucrase-isomaltase (SI) in regulating dietary behaviours, such as sweet preference and food liking in Si knockout (Sis-KO) mice and in population-based cohorts from Greenland and the UK. DesignWe profiled the appetitive and post-ingestive response to dietary carbohydrates in SI knockout (Sis-KO) mice. Alongside this, we conducted detailed dietary analysis of 45 foods in two Greenlandic population-based cohorts (IHIT, n=2778 and 68 foods, and B2018, n=2203 and 45 foods) with the presence of a common (allele frequency = 14.3%) SI Loss of function (LoF) variant, c.273-274delAG. Finally, we explored the association between SI hypomorphic variants, liking of 140 foods, and sucrose content using data from 134,766 UKBB participants with exome sequencing and questionnaire data available. ResultsSucrose naive Sis-KO mice had a significantly reduced intake of dietary sucrose, and preference for 10% liquid sucrose, in two-bottle preference studies. Mechanistically, oral administration of the short-chain fatty acid acetate reduced sucrose-preference in wild-type mice. In Greenlandic LoF homozygous carriers we show that the previously reported reduction in sugar intake may primarily be explained by a lower intake of cake and pastries, and of candy and chocolate and that added sugar is the main factor explaining these associations. In the UKBB, a negative association with "cake icing", the food with the highest sucrose content per 100g, was detected in SI hypomorphic carriers, as well as in sensitivity analyses conducted only including carriers of known CSID LoF variants. Further, a negative linear relationship was also observed between the effect estimates of hypomorphic SI variants on food liking and the estimated sucrose content per 100g of 88 sucrose-containing foods, indicating that food dislike in SI carriers correlates with the amount of sucrose in food. ConclusionCollectively, we demonstrated that genetic variation in the SI gene is associated with significant changes in sucrose preference, characterised by a rapid avoidance of dietary sucrose in Sis-KO mice, as well as lower consumption and increased disliking of sucrose rich foods in Greenlanders and Europeans, respectively. This work demonstrates that genetic variation in the SI gene may impact physiology beyond the gastrointestinal tract and suggest the possibility to target SI to reduce the preference, and intake, of dietary sucrose with implications for digestive and metabolic health.

genetics↗

bioRxiv2024

FGF21 deletion mildly exacerbates hepatic dysfunction in MASH diet and alcohol fed rats

ObjectiveFibroblast growth factor 21 (FGF21) is a hepatokine that improves dyslipidemia, steatosis, inflammation, and fibrosis. FGF21 analogues are in clinical development as treatments for metabolic and alcohol-associated liver disease, creating a need for new models to help understand FGF21 physiology and drug mechanisms of action. The aim of this study was to create and initially characterize the first FGF21 knockout (KO) rat line to validate its utility as a translational animal model that recapitulates human MASH and ALD, and to provide a resource for examining FGF21-related phenotypes that are more appropriate for the rat. MethodsWe generated an FGF21 KO rat model using CRISPR/Cas9 to insert an artificial STOP codon in exon 1 and exposed 6-month-old WT and KO rats to either chow (n=8 per genotype) or the GAN (Gubra Amylin NASH) diet (n=16 per genotype) for 12 weeks. We further evaluated alcohol drinking behavior and biochemistry in FGF21 KO and WT rats. In the diet model, we further analysed liver and blood biochemistry in addition to histopathological scoring of NAFLD activity score (NAS), fibrosis stage and the liver transcriptome for in-depth characterization of the model. ResultsLack of endogenous FGF21 increased plasma transaminases, liver weight, and total levels of liver TG in GAN-fed FGF21 KO rats. FGF21 deletion also increased ALT in alcohol-fed FGF21 KO rats. However, in the GAN diet model, FGF21 KO had no impact on body weight, fat mass, glycaemic traits, MASH histological endpoints including hepatic steatosis, NAS score, lobular inflammation, ballooning degeneration or fibrosis stage after 12 weeks. Similarly, there was no effect of the loss of endogenous FGF21 on the liver transcriptome in response to GAN diet feeding. Finally, we demonstrate that endogenous FGF21 does not regulate drinking behaviour in rats. ConclusionFGF21 deficiency accelerates hepatic dysfunction in diet and alcohol-induced liver disease models in rats, providing support from a new species that FGF21 might be a hepatoprotective factor.

physiology↗

bioRxiv2019

Standard housing temperature but not β3-adrenoreceptor agonism drives weight-gain and adipose tissue deposition in rats following diet induced obesity at thermoneutrality

Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality ([~]20{degrees}C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold-exposure and {beta}3-adrenoreceptor agonism under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28{degrees}C to 20{degrees}C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in IWAT in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e. G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e. eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.

physiology↗

bioRxiv2019

Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT

Background and aimExercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents. However, these animals are typically housed below their thermoneutral zone (i.e. 28-32{degrees}C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28{degrees}C (i.e. thermoneutrality) on BAT and WAT in its basal (i.e. inactive) state.\n\nMethodsSprague-Dawley rats (n=12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet (HFD). At 12 weeks of age half these animals were randomised to 4-weeks of exercise exercise training, i.e. swim-training (1 hour/day, 5 days per week). Metabolic assessment was undertaken during the final 48h and was followed by interscapular and perivascular BAT and inguinal (I)WAT sampling for the analysis of thermogenic genes and the proteome.\n\nResultsExercise attenuated weight gain but did not affect fat mass or general metabolic parameters (i.e. fasting insulin and glucose). Interestingly, although BAT mass was increased, there was no change in thermogenic gene expression. Differentially regulated proteins in BAT enriched gene ontology (GO) terms including 2-oxoglutarate metabolic process, cytochrome-c activity and mitochondrial respiratory chain complex IV. This was accompanied by an upregulation of multiple proteins and GO terms involved in skeletal muscle physiology suggesting an adipocyte to myocyte switch in BAT. UCP1 mRNA was undetectable in IWAT despite an increase in classical browning markers (i.e. PGC1a and ADRB3) with exercise. Enriched GO terms in IWAT included DNA binding and positive regulation of apoptosis. Impact analysis highlighted carbon metabolism and OXPHOS pathways were regulated by exercise in BAT whilst HIF-1 signalling and cytokine-cytokine receptor interaction were among those modified in IWAT.\n\nConclusionExercise training reduces weight gain in obese animals at thermoneutrality and is accompanied by an oxidative, myogenic signature in BAT, rather than induction of thermogenic genes. This may represent a new, UCP1-independent pathway through which BAT regulates body weight at thermoneutrality.

physiology↗