Summary: The liver appears to play an important role in regulating eating behavior in mice.
A new Yale study has found that the liver plays an important role in regulating eating behavior in mice, a discovery that could have implications for people with eating disorders and metabolic diseases.
The study, conducted in collaboration with colleagues in Germany, also adds to a growing body of evidence showing that the most advanced part of the brain, the cerebral cortex, is influenced by the rest of the body, and not just the other way around.
“One takeaway from this work is that the classic attempt to understand brain function by looking only at the brain itself does not provide a complete picture,” said Tamas Horvath, Jean and David W. Wallace Professor of Comparative Medicine at the Yale School of Medicine and senior author of the study published June 27 natural metabolism.
In a series of experiments, the research team discovered a circuit that allows the brain and liver to communicate and control each other. The two main participants in this conversation are a group of cells known as agouti-related protein (AgRP) neurons, found in the hypothalamus region of the brain, and a type of lipid secreted by the liver called lysophosphatidylcholine (LPC) is called.
AgRP neurons, which communicate with the cerebral cortex, the outer layer of the brain associated with complex behaviors and skills, are essential in promoting feelings of hunger. But they also communicate with other parts of the body, like the liver and pancreas; When people are hungry, these neurons play a crucial role in releasing lipids from the body’s fat stores.
Once LPC is secreted by the liver, an enzyme in the blood quickly converts it to lysophosphatidic acid, or LPA. Other researchers have shown that LPA can alter neuronal activity in the brain.
In this study, the researchers observed that fasting mice had higher levels of LPA in both their blood and cerebrospinal fluid, the special fluid in the central nervous system. This increase in LPA levels caused an increase in neural activity in the cortex, triggering an increased appetite after fasting. And all of these effects were dependent on AgRP neuron function.
These results suggest a circuit in which AgRP neurons regulate liver and lipid release, and in which these lipids circulate back to the brain, where they affect the cortex and its functions.
Horvath says more research is needed to determine if a similar circuit exists in humans, but he and his colleagues found some evidence that it might.
Mice that experience a mutation that results in greater LPA-induced neuronal activity eat more and weigh more than their typical mouse counterparts. People with the same genetic mutation tend to have higher body mass index and a greater prevalence of type 2 diabetes than people without the mutation.
“We still need to investigate further whether these mechanisms are relevant to humans, but if so, we can start to investigate whether we can use the mechanisms to treat eating disorders and other diseases,” Horvath said.
“But this shows that the liver can be an important driver of behavior. And it adds to the argument that staying in the brain is not enough to understand the brain.”
Other Yale authors of the study are Bernardo Stutz, Zhong-Wu Liu and Matija Sestan-Pesa.
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Author: Mallory Locklear
Contact: Mallory Locklear-Yale
Picture: The image is in the public domain
Original research: Closed access.
“AgRP neurons control feeding behavior at cortical synapses via peripherally derived lysophospholipids” by Heiko Endle et al. natural metabolism
AgRP neurons control feeding behavior at cortical synapses via peripherally derived lysophospholipids
Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown.
Here we show that concentrations of lysophosphatidic acid (LPA) species in blood and cerebrospinal fluid are elevated after overnight fasting and result in higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia and is decreased after inhibition of LPA synthesis.
Mice carrying a human mutation (Prg-1R346T), resulting in higher synaptic lipid-mediated cortical excitability, shows increased fasting-induced hyperphagia. Accordingly, people with this mutation have a higher body mass index and a higher prevalence of type 2 diabetes.
We further show that the post-fasting effects of LPA are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation in circulating LPAs as well as cortical excitability while blunting hyperphagia.
These results demonstrate a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability and unveil an alternative non-neuronal pathway through which the hypothalamus can exert a powerful influence on the cortex and thereby influence food intake.