Biology subjects

Tung, Y. C. L.

Publications and source records attributed to Tung, Y. C. L..

3 recordsLinked to original sources

bioRxiv2020

A multi-component screen for feeding behaviour and nutritional status in Drosophila to interrogate mammalian appetite-related genes

More than 300 genetic variants have been robustly associated with measures of human adiposity. Highly penetrant mutations causing human obesity do so largely by disrupting satiety pathways in the brain and increasing food intake. Most of the common obesity-predisposing variants are in, or near, genes that are expressed highly in the brain, but little is known about their function. Exploring the biology of these genes at scale in mammalian systems is challenging. We therefore sought to establish and validate the use of a multicomponent screen for feeding behaviour and nutrient status taking advantage of the tractable model organism Drosophila melanogaster. We validated our screen by demonstrating its ability to distinguish the effect of disrupting neuronal expression of four genes known to influence energy balance in flies from ten control genes. We then used our screen to interrogate two genetic data sets. Firstly, we investigated 53 genes that have been implicated in energy homeostasis by human genome wide association studies (GWASs): of the 53 Drosophila orthologues studied, we found that 16 significantly influenced feeding behaviour or nutrient status. Secondly, we looked at genes which are expressed and nutritionally responsive in specific populations of hypothalamic neurons involved in feeding/fasting (POMC and AgRP neurons): 50 Drosophila orthologues of 47 murine genes were studied, and 10 found by our screen to influence feeding behaviour or nutrient status in flies. In conclusion, Drosophila provide a valuable model system for high throughput interrogation of genes implicated in feeding behaviour and obesity in mammals. Author SummaryNew high-throughput technologies have resulted in large numbers of candidate genes that are potentially involved in the control of food intake and body-weight, many of which are highly expressed in the brain. How, though, are we to find the functionally most relevant genes from these increasingly long lists? Appetite needs to be explored in context of a whole animal, but studies in humans and mice take a long time and are expensive. The fruit fly, while clearly evolutionarily distant, shares a surprising amount of biology with mammals, with 75% of genes involved in inherited human diseases having an equivalent in flies. In particular, the fruit fly has surprisingly conserved neuronal circuitry when it comes to food intake. Here we have developed a suite of four different functional assays for studying the feeding behaviour and energy balance in flies. We then used these assays to explore the effects of disrupting the expression of genes in the neurons of flies, that either are implicated in body weight through human genetic studies or are expressed and nutritionally responsive in specific populations of neurons involved in feeding. We show that the use of fruit flies are time and cost efficient, and are a valuable model system for studying genes implicated in feeding behaviour and obesity in mammals.

physiology↗

bioRxiv2019

GDF15 and the beneficial actions of metformin in pre-diabetes

Metformin, the worlds most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk, by lowering body weight, fat mass and circulating insulin levels through mechanisms that are incompletely understood. Recent observational studies reporting the association of metformin use and circulating levels of GDF15 led us to hypothesize that GDF15, which signals through a specific receptor complex in the hindbrain to reduce body weight, might mediate these effects. We measured GDF15 in people without diabetes from a randomized placebo-controlled trial of metformin. Over 18 months, participants allocated metformin lost significant weight and levels of GDF15 were persistently elevated compared to placebo. The change in plasma GDF15 in this study correlated positively with weight loss. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. The insulin sensitising effects of metformin determined by insulin tolerance were abolished in mice lacking GDF15. Metformin significantly reduced fasting glucose and insulin levels in wild type but not in mice lacking GDF15. In summary, metformin increases the circulating levels of GDF15, which appears to be necessary for many of its actions as a metabolic chemopreventive agent.

physiology↗

bioRxiv2017

Loss And Gain Of Function Experiments Implicate TMEM18 As A Mediator Of The Strong Association Between Genetic Variants At Human Chromosome 2p25.3 And Obesity

An intergenic region of human Chromosome 2 (2p25.3) harbours genetic variants which are among those most strongly and reproducibly associated with obesity. The molecular mechanisms mediating these effects remain entirely unknown. The gene closest to these variants is TMEM18, encoding a transmembrane protein localised to the nuclear membrane. The expression of Tmem18 within the murine hypothalamic paraventricular nucleus was altered by changes in nutritional state, with no significant change seen in three other closest genes. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We confirmed the nuclear membrane localisation of TMEM18 but provide new evidence that it is has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.

physiology↗