Biology subjects

Gillum, M. P.

Publications and source records attributed to Gillum, M. P..

5 recordsLinked to original sources

bioRxiv2026

Proteomic profiling of experimental acute alcohol intoxication reveals FGF21 as a specific ethanol-induced hormone

Background: The effects of acute alcohol intoxication on the human plasma proteome are still largely unexplored. Gaining insights into this relationship could identify factors that are influenced by and influence alcohol consumption. Fibroblast Growth Factor 21 (FGF21), a hormone produced by the liver and associated with alcohol preferences, is currently undergoing Phase 2 clinical trials for metabolic dysfunction and alcohol-related liver disease. We hypothesized that FGF21 is a key endocrine responsive hormone to alcohol in humans. Methods: In a post hoc analysis, we evaluated the effects of five standard units of alcoholic beverages on the plasma proteome in 12 healthy Caucasian men. Participants, fasting for 10 hours, received 0.7 g of alcohol per kg of body weight via gastric infusion, with blood samples collected before and after consumption. Results: The proteomic response to this level of alcohol intoxication was highly specific. Of 1,462 proteins measured, only 11 changed significantly and FGF21 exhibited by far the largest increase (10.5-fold). Conclusion: This study highlights a unique proteomic response to acute alcohol ingestion and supports further exploration of FGF21 mimetics as potential treatments for alcohol-related disorders.

physiology↗

bioRxiv2026

A loss-of-function variant in GFRAL associates with increased alcohol consumption in humans

Alcohol is an ancient and enduring component of the human diet, yet it is a dose-dependent cytotoxin and teratogen, raising the possibility that endogenous, state-dependent mechanisms constrain intake. Growth differentiation factor 15 (GDF15) is an endocrine hormone that rises during pregnancy--predominantly via secretion from blastocyst-derived placental trophoblasts into the maternal circulation--and is also induced in other tissues, particularly hepatocytes, by toxins and cellular stress. However, its function in humans remains unclear. Here, we show that circulating GDF15 levels are elevated 5-fold in individuals with alcohol dependence, identify a rare loss-of-function variant in the GDF15 receptor gene GFRAL associated with approximately 2.6 additional UK alcohol units ([~]21 g ethanol) per week, and demonstrate that recombinant GDF15 reduces alcohol drinking in mice. Collectively, these findings support a model in which GDF15 acts as an endocrine signal induced by chronic alcohol exposure--and potentially during pregnancy--to limit alcohol intake in humans. HighlightsO_LIGDF15 is markedly elevated in humans with alcohol dependence C_LIO_LIA truncating GFRAL variant associates with higher alcohol intake in UK Biobank C_LIO_LIGFRAL frameshift disrupts GDF15-RET signaling in vitro C_LIO_LIRecombinant GDF15 suppresses voluntary alcohol intake in mice C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/709997v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@13630fborg.highwire.dtl.DTLVardef@c9bebforg.highwire.dtl.DTLVardef@109fd63org.highwire.dtl.DTLVardef@da971f_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

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↗

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↗