Biology subjects

Grevengoed, T. J.

Publications and source records attributed to Grevengoed, T. J..

3 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↗

bioRxiv2020

Cardiomyocyte-specific ACSL1 Deficiency Prevents Cardiac Lipotoxicity and Alleviates Heart Dysfunction in the ob/ob Model of Obesity

Cardiac lipotoxicity is associated with structural remodeling and functional changes that are features of obesity-related cardiomyopathy. Both high fat diet and the ob/ob mutation lead to increased fatty acid (FA) uptake, elevated triacylglycerol (TAG) content, hypertrophy, and systolic and diastolic dysfunction in murine hearts. Cardiomyocyte-specific long-chain acyl-CoA synthetase 1 (ACSL1) deficiency (Acsl1H-/-) results in a 90% reduction in FA activation, suggesting that Acsl1 ablation might alleviate obesity-associated myocardial dysfunction. Double knockout ob-Acsl1H-/- and ob-Acsl1flox/flox control mice were treated with tamoxifen at 20 weeks of age; heart function, TAG content, and relevant gene expression were assessed immediately before and 2 and 5 weeks after treatment. Heart weights initially increased in lean and obese Acsl1H-/- mice, but normalized in ob-Acsl1H-/- mice by 5 weeks. Ventricular TAG content was decreased by 51% and 61% in ob-Acsl1H-/- mice 2 and 5 weeks after Acsl1 knockout induction, respectively. Moreover, ACSL1 knockout resulted in increased survival of ob/ob mice, suggesting that lack of ACSL1 protected obese hearts subjected to stress. Our results indicate that partial knockdown of cardiac ACSL1 is sufficient to reverse cardiac TAG accumulation and to ameliorate heart dysfunction even in the context of established obesity-related cardiomyopathy.

physiology↗

bioRxiv2018

FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

ObjectiveExcessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes {beta}-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain.\n\nMethodsWe recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma. In addition, we measured circulating FGF21 (1-181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice.\n\nResultsWe show that alcohol ingestion (25.3 grams or ~2.5 standard drinks) acutely increases plasma levels of FGF21 (1-181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1-181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1-181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice.\n\nConclusionsFGF21 (1-181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans.

physiology↗