Summary: New evidence from mice indicates the liver helps regulate feeding behavior by releasing lipids that influence brain activity.
Source: Yale
A team of researchers at Yale University, working with collaborators in Germany, reports that the liver plays a major and previously underappreciated role in controlling feeding behavior in mice. The findings, published June 27 in Nature Metabolism, may have implications for understanding human eating disorders and metabolic diseases.
This study adds to growing evidence that the brain, including its most advanced regions such as the cerebral cortex, does not act in isolation. Instead, peripheral organs like the liver send signals back to the brain and modulate neural circuits that determine appetite and food intake.
“One clear takeaway is that studying brain function only within the brain gives an incomplete picture,” said Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine at Yale School of Medicine and a senior author on the paper.
Through a series of experiments, the researchers mapped a communication loop between the brain and liver. Central to this loop are hypothalamic agouti-related peptide (AgRP) neurons—cells known to promote hunger—and a class of liver-derived lipids called lysophosphatidylcholines (LPCs). After LPCs are released into the bloodstream, they are rapidly converted by circulating enzymes into lysophosphatidic acids (LPAs), lipid molecules that can alter neuronal excitability.
AgRP neurons are critical regulators of hunger and are connected to many brain regions, including the cerebral cortex, which controls higher-order behaviors. These neurons also influence peripheral organs such as the liver and pancreas; when the body signals energy need, AgRP neurons help mobilize lipid stores. The Yale-led team found that when the liver secretes LPCs, their conversion to LPA increases LPA levels in both blood and cerebrospinal fluid, and these elevated LPA concentrations raise cortical neuronal activity.
The researchers observed that overnight fasting produced a measurable increase in LPA species in both circulation and the cerebrospinal fluid of mice. That rise in LPA correlated with heightened cortical excitability and a stronger feeding response once food was returned. Importantly, these fasting-induced effects depended on the presence and activity of AgRP neurons: disrupting AgRP neuron function reduced circulating LPA after fasting, lowered cortical excitability, and blunted the post-fasting hyperphagia.
Taken together, the data support a model in which hypothalamic AgRP neurons regulate peripheral lipid release from the liver, and those lipids then feed back to the brain—specifically the cortex—to influence eating behavior. This establishes a two-way, non-neuronal pathway by which the hypothalamus can exert significant control over cortical function and drive food intake.
The team also examined genetic evidence linking this mechanism to metabolic outcomes. Mice carrying a mutation that enhances LPA-driven cortical excitability consumed more food after fasting and showed higher body weight compared with wild-type controls. Human carriers of the same mutation (PRG-1 R346T) are reported to have higher average body mass index and an increased prevalence of type 2 diabetes relative to noncarriers, consistent with a conserved influence of LPA-related signaling on metabolism.
“We need further research to determine how closely this circuit operates in humans,” Horvath said. “If similar mechanisms exist in people, they could offer new targets for treating eating disorders, obesity, and related metabolic conditions. At minimum, these findings highlight that focusing exclusively on the brain is insufficient to fully understand the neural control of feeding.”
Other Yale co-authors on the paper include Bernardo Stutz, Zhong-Wu Liu, and Matija Sestan-Pesa.
About this neuroscience and behavior research news
Author: Mallory Locklear
Source: Yale
Contact: Mallory Locklear – Yale
Image: The image is in the public domain
Original Research: Closed access.
“AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids” by Heiko Endle et al. Nature Metabolism
Abstract
AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids
Phospholipid profiles are shaped by peripheral metabolic state, and within the central nervous system, synaptic phospholipids influence glutamatergic transmission and cortical excitability. Whether peripheral metabolic changes alter brain lipid levels and thereby modulate cortical function has been unclear.
This study shows that levels of specific lysophosphatidic acid (LPA) species rise in blood and cerebrospinal fluid after overnight fasting, and that these increased LPAs enhance cortical excitability. The LPA-driven increase in cortical activity amplifies fasting-induced overeating, while inhibiting LPA synthesis reduces this effect.
Mice engineered to express a human PRG-1 R346T mutation, which increases synaptic lipid-mediated cortical excitability, exhibit greater fasting-induced hyperphagia. Correspondingly, human carriers of this mutation display higher body mass index and a greater prevalence of type 2 diabetes.
Finally, the authors demonstrate that hypothalamic AgRP neurons control these LPA-dependent effects: selective depletion of AgRP-expressing cells in adult mice lowers fasting-associated increases in circulating LPAs and cortical excitability, and it diminishes post-fasting hyperphagia.
These results reveal a non-neuronal feedback loop in which hypothalamic AgRP neurons regulate peripheral LPA levels that, in turn, directly influence cortical excitability and feeding behavior.