GDF15 signals nutritional stress

Abstract

Growth differentiation factor 15 (GDF15) is a well-established marker of cellular stress. Interestingly, mice that lack GDF15 are more susceptible to diet-induced obesity. Moreover, the receptor for GDF15 was recently discovered to be specifically expressed in the brain stem; these observations suggested a role for GDF15 in metabolism. A new study reports that nutritional stress increases levels of GDF15, which might mediate an aversive dietary response. The researchers first showed that in healthy human volunteers, GDF15 levels are unaffected by eating a meal, by ingesting glucose or by short-term hypercaloric feeding. Moreover, in mice and humans, fasting or caloric restriction had no effect on GDF15. To test the effect of long-term stress on GDF15 levels, mice were fed either a normal chow diet or a high-fat diet (HFD) over a sustained period. After 8 weeks, mice on a HFD had elevated plasma levels of GDF15 and increased GDF15 mRNA expression in the liver, in white epididymal adipose tissue and in brown adipose tissue. In addition, mice fed a lysine-deficient diet had increased GDF15 levels compared with control animals, thereby showing that other nutritional stressors had an effect. In vitro studies using wellcharacterized inducers of the cellular integrated stress response (ISR) showed that GDF15 expression is regulated by the ISR. Moreover, the GDF15 induction pathway was shown to involve activation of the kinase EIF2α and downstream increases in expression of the transcription factors ATF4 and CHOP. In support of this finding, mice fed a lysine-deficient diet had increased levels of GDF15, ATF4 and CHOP mRNA in the liver compared with control animals. Administering GDF15 to mice resulted in a dose-dependent reduction of food intake, as shown in previous studies. Notably, however, mice that were treated with GDF15 showed conditioned taste aversion, as determined by a two bottle saccharin preference test. Conditioned taste aversion occurs when an animal associates the taste of a normal food with symptoms caused by an aversive substance. These findings indicate that GDF15 might elicit an aversive food response in mice. “Dietary stresses increase the production of GDF15, which may then provide an aversive signal to the brain,” corresponding authors David Savage and Stephen O’Rahilly conclude. “This may provide some ‘brake’ on the ingestion of the diet that induced the stress in the first place.” This study might inform future research into human disease. “GDF15 levels are increased in a broad range of human pathologies,” say Savage and O’Rahilly. “More knowledge is needed to better understand how this is related to changes in appetite and cachexia in these conditions.” Shimona Starling research has linked anxiety disorders with body weight change in humans, but the precise relationship between them is unclear. For example, the persistent activation of the sympathetic nervous system could result in increased energy expenditure via heightened adaptive thermo genesis, but high levels of glucocorticoids (which are common in anxiety disorders) could result in increased visceral adiposity. Now, new research by Baoji Xu and colleagues has revealed a link between anxiety and hyper-metabolism. The authors found that increases in the activation of anxiogenic circuits can reduce body weight via the promotion of adaptive thermogenesis and basal metabolism. The researchers note that this is the first study to report this link. “although two papers show an association between anxiety disorders and extra weight gain in children, we did not find any published studies that examine if and how anxiety affects metabolism and body weight,” adds Xu. Xu and his team are interested in the role of brain-derived neurotrophic factor (BDNF) in the control of energy balance. “We and others have shown that mutations in the gene for BDNF or its receptor, TrkB, lead to marked hyperphagia and severe obesity in both humans and mice,” explains Xu. “In this study, we aimed to identify the BDNF-expressing brain areas that are involved in the regulation of energy balance.” In the present study, the investigators knocked out Bdnf in specific brains regions of mice using region-specific gene deletion. Xu and colleagues then used behavioural and biochemical analyses to study their mouse model. They found that the deletion of Bdnf in the dorsal forebrain resulted in a lean mouse that was resistant to obesity when fed a high-fat diet. “Further analyses of the mutant mice led us to realize a link between anxiety and hyper-metabolism; thus, this was a discovery by serendipity,” adds Xu. The team report that elevated adaptive thermogenesis in their mouse model was accompanied by increased food intake, while elevated basal metabolic rate did not affect food intake. “This observation suggests that it could be a more effective therapy for obesity to increase the basal metabolic rate than to elevate adaptive thermogenesis,” explains Xu. he does note, however, that more studies are necessary to substantiate this view. Xu hopes that the present study might help us understand why people with anxiety sometimes report weight loss. “We are interested in the neural circuit that links anxiety to increased energy expenditure” concludes Xu. “I think that a good strategy for treating obesity could be to target parts of this neural circuit (of course, without affecting mood).”