New findings published in the journal Cell show that sensory food perception is sufficient to activate signalling in the mouse liver that results in morphological endoplasmic reticulum (ER) remodelling in anticipation of the metabolic changes required for nutrient intake.

Credit: Sebastian Kaulitzki/Alamy Stock Photo

To prepare the body for food consumption and the disturbance to internal homeostasis, a set of physiological changes termed the cephalic phase are elicited by the sight, smell and taste of food. Mediated by the autonomic nervous system, these changes ensure rapid and efficient digestion and metabolism of nutrients. The liver experiences its own set of changes during the transition from a fasted to a fed state. Elevated circulating levels of nutrients activate hepatic mechanistic target of rapamycin (mTOR) signalling and the accumulation of unfolded proteins in the ER promotes stress responses that include the splicing of Xbp1 mRNA to promote ER expansion. Although many aspects of the cephalic phase have been described, few studies have examined how these responses might be effected in peripheral organs. The latest study aimed to establish a role for the central nervous system in coordinating liver nutrient responses and to determine if the sight and smell of food are sufficient to prime the liver.

The researchers first examined changes in the liver transcriptome induced by food perception, using mice that were fasted and then either allowed to eat or presented with inaccessible caged food that could be seen or smelled but not consumed. Analysis of hepatic mRNA expression showed clear differences between fasted and refed mice, and mice exposed to caged food compared to refed mice. Analysis of gene expression changes showed that ER stress responses mediated by XBP1 were the primary transcriptional programmes activated by food cues.

A phosphoproteomic screen performed on liver tissue from the different groups showed rapid mTOR phosphorylation in the livers of mice after only 5 mins of food perception or refeeding. Characterization of hepatic lipid profiles also showed separation between fasted mice and either refed mice or mice exposed to caged food. The key lipid classes contributing to this effect were products of enzymes that are key targets of mTOR and XBP1 regulation. The investigators also examined changes in ER morphology using electron microscopy and observed rapid hepatic ER remodelling and elongation in refed mice or those exposed to caged food.

After demonstrating that food perception can prime hepatic ER responses, the team investigated whether this regulation might be linked to changes in energy-sensing pro-opiomelanocortin (POMC)-expressing neurons in the hypothalamus. Using fibre photometry, POMC neuron activity was shown to rapidly and transiently increase in response to food perception but not fake food exposure. Then, by optogenetically activating POMC neurons and examining liver tissue in mice, the team found that POMC neuron stimulation induced hepatic mTOR signalling and spliced Xbp1 expression. These responses were attenuated in mice deficient in the melanocortin 4 receptor. Finally, using chemogenetic approaches, the researchers showed that POMC-neuron activation, as observed upon food perception, promotes hepatic sympathetic nerve activity and that noradrenaline released from sympathetic nerve endings stimulates mTOR signalling and Xbp1 splicing in hepatocytes in vitro.

Together, these findings reveal how food perception is relayed from the hypothalamus to the liver to induce an early ER stress response via mTOR and XBP1 activation that then primes the liver for incoming nutrients. Looking ahead, the researchers are interested in determining how this response might be compromised in obesity and what role it has in ageing-related diseases that are associated with ineffective proteostasis processes.