Food taste and odor triggered mitochondrial fragmentation in liver cells in mice
German scientists found in in vitro and in vivo experiments that sensory perception of food rapidly induced mitochondrial fragmentation in the liver via protein kinase B/Akt-dependent phosphorylation of mitochondrial fission factor serine 131 (MFFS131). This response was triggered by activation of hypothalamic proopiomelanocortin-expressing neurons (POMC neurons) and promoted insulin sensitivity. The results of the study are published in the journal Science.
The brain phase of digestion, in which gastric secretion and various metabolic pathways are triggered in response to conditionally reflexive stimuli (e.g., the smell and sight of food), allows the body to respond quickly to anticipated metabolic "tasks." However, the neural and molecular mechanisms underlying the regulation of anticipatory changes in the liver during the transition from fasting to food intake remain only partially understood. It is known that the key regulators of eating behavior and modifiers of glucose and lipid metabolism in the liver are neurons of the arcuate nucleus of the hypothalamus - AgRP-neurons and neurons expressing proopiomelanocortin (POMC-neurons).
It was previously thought that they gradually and slowly modulate their activity with endocrine feedback signals from the periphery, but now scientists know that these neurons are rapidly activated by sensory perception of food for prognostic tasks. Moreover, it is the POMC neurons that act as the most important mediator of the brain phase. However, the role of these neurons in the regulatory mechanisms of mitochondrial dynamics of liver cells, which has a significant impact on systemic and hepatic glucose metabolism and on the development of insulin resistance, is not fully understood.
A research group led by Jens Brüning (Jens Brüning) from the Institute for Metabolism Research of the Max Planck Society conducted a series of in vitro and in vivo experiments to find out how stimulation of POMC-neurons by the smell and taste of food affects the activity of liver mitochondria. The scientists first tested by phosphoproteomic analysis whether sensory perception of food was sufficient to alter protein phosphorylation in liver mitochondria. To do this, mice were starved for 16 hours, then allowed to see and feel food in an inaccessible cage for 5, 10, or 30 minutes. Other starved mice were allowed to consume food. Both food perception and food ingestion resulted in increased levels of mitochondrial fission factor serine 131 phosphorylation (mouse MFF Uniprot accession Q6PCP5 - MFFpS131), equivalent to human MFFpS157, throughout the 5, 10, and 30 minute time periods following food consumption in the cage.
The scientists then examined phosphorylation processes in mouse liver during optogenetic activation of POMC neurons after six hours of fasting. This exposure led to similar phosphorylation clusters in the same region of MFFpS131, which is activated during sensory perception of food and food intake. Since the mitochondrial fission factor under investigation is known to play a crucial role in modulating mitochondrial dynamics and architecture, the researchers also examined mitochondrial morphology during sensory perception of food and ingestion using transmission electron microscopy. It turned out that sensory perception of food was enough to induce changes in mitochondrial morphology within minutes similar to those receiving food. The same was observed with optogenetic activation of POMC neurons.
Further analysis showed that changes in phosphorylation activity in liver mitochondria during sensory perception of food were associated with activation of protein kinase B/AKT. To determine the functional consequences of MFFS131 phosphorylation, the scientists created two modified mouse models: one line of mice in which MFFS131 cannot be phosphorylated and another line in which constant phosphorylation of MFFS131 is mimicked.
Mice in which phosphorylation did not occur exhibited a more fused mitochondrial network compared to control animals; in contrast, high levels of phosphorylation promoted greater fragmentation of the liver mitochondrial network. Mice with a homozygous non-phosphorylatable MFFS131 mutation did not show any changes in body weight, body composition or glucose tolerance compared to controls, but did show a moderate decrease in insulin sensitivity.
The scientists conclude that AKT-dependent phosphorylation of MFFS131 and dynamic mitochondrial fragmentation are required for effective insulin-induced suppression of liver glucose production. In the future, the development of therapeutic approaches in the treatment of diabetes and obesity based on the effects on these molecular mechanisms is possible.