Animals utilize distinct neural circuits for body weight maintenance via integration of hormonal and metabolic signals to balance energy expenditure and food intake. Brown Adipose Tissue (BAT) maintains metabolic balance via diet-induced thermogenesis. Growth Differentiation Factor 15 (GDF15) drives weight loss and reduces food consumption, but its impact on energy expenditure is unknown. GDF15 is elevated in a range of conditions with increased nausea and feeding aversion such as cachexia and pregnancy. GDF15 signals through its receptor GFRAL, expressed solely in the brainstem areas, the area postrema (AP) and nucleus of the solitary tract (NTS). Evidence suggests GFRAL activation may activate the lateral parabrachial nucleus and central amygdala, areas of brain associated with fear and feeding aversion.
To investigate how GDF15 signalling impacts on BAT thermogenesis and innate and learned responses to tastes, C57black/6 mice were stereotaxically injected into the NTS with an AAV to overexpress GDF15. Following this, mice were assessed for anxiety-like behaviour, conditioned taste aversion (CTA) to lithium chloride and saccharin preference. Mice were also implanted with radio-telemeters into the interscapular BAT for continuous monitoring of BAT temperature and locomotor activity during baseline and metabolic manipulations.
GDF15 overexpression resulted in a failure to adaptively decrease thermogenesis during fasting, and a suppression of food intake upon refeeding. Complete behavioural categorization of all time spent in a baited open field shows mice behave similarly during the test. GDF15-overexpressing mice have increased sensitivity to a CTA associated lithium chloride. They also show decreased preference for sweet taste (0.1% saccharin or water; two bottle choice) compared to controls, however this normalises after three days of exposure to the paradigm. This indicates increased sensitivity to aversive responses to taste, and decreased sensitivity to pleasurable taste – supporting the idea that elevated GDF15 may shift negatively impact emotional responses to feeding stimuli.