For years, scientists have considered starvation regulation as a tug-of-war between two kinds of neurons within the hypothalamus: those who specific the AGRP gene and improve starvation, and those who specific the POMC gene and act as a brake. Now a brand new research challenges this long-standing mannequin, revealing a 3rd participant within the hunger-satiety community—a neuron sort that expresses the BNC2 gene and suppresses starvation sooner than those who specific POMC.
These BNC2 neurons are activated by leptin—a hormone that helps suppress urge for food and increase metabolism. Their discovery “reshapes our understanding of feeding conduct,” says lead investigator Han Tan, “and the way leptin regulates physique weight.” Tan is a analysis affiliate in Jeffrey Friedman’s lab at Rockefeller College.
“We’ve identified for a very long time there should be [other] neurons within the mind which can be sensing leptin and reducing urge for food, however we didn’t know who they have been till now,” says John Campbell, assistant professor of biology on the College of Virginia, who wasn’t concerned within the research.
The outcomes jibe with two different latest studies of leptin-sensitive neurons within the arcuate nucleus—a area within the hypothalamus that processes indicators associated to starvation and satiety. The neurons generate emotions of fullness, an impartial workforce reported in Science in June, they usually dampen urge for food by inhibiting AGRP-expressing “starvation neurons,” based on a research Campbell and his colleagues printed in Nature Metabolism in December 2024.
The research all level to a singular group of neurons that inhibit starvation, says Martin Myers, professor of inside drugs and molecular and integrative physiology on the College of Michigan, who was not concerned within the work. “The three teams primarily discovered [these neurons] concurrently.”
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nterest in leptin-sensitive neurons started about 30 years in the past, when Friedman and his colleagues found the leptin hormone. Produced by fats cells, leptin informs the mind about vitality shops within the physique, and mice with mutations within the leptin gene or its receptor turn into severely overweight.
Till not too long ago, AGRP and POMC neurons have been thought of leptin’s fundamental targets. However activating AGRP neurons rapidly triggers urge for food, whereas POMC neurons take hours to suppress starvation. That hole urged one thing was lacking, Tan says.
To search for different cells that specific leptin receptors in mice, Tan and his colleagues turned to a way that measures gene expression by sequencing RNA from particular person nuclei. The BNC2 neurons they recognized activate inside seconds after a fasted mouse sees meals and ultimately inhibit AGRP neurons, selling satiety. The researchers printed their findings in Nature in October.
“AGRP and BNC2 neurons are the yin-yang for starvation and satiety,” Tan says, whereas POMC neurons probably play a task within the long-term regulation of physique weight.
“It took a bit little bit of fancy footwork and the appliance of a good quantity of know-how to determine [BNC2] neurons,” Myers says. The cells additionally specific the GLP-1 receptor—a goal of well-liked weight-loss medication comparable to semaglutide (generally marketed as Ozempic)—and could possibly be vital for pharmacological interventions to manage urge for food, he says. However, he provides, it’s unclear whether or not these neurons contribute to the day by day regulation of meals consumption or in the event that they’re vital solely throughout instances of utmost starvation, comparable to in fasted animals.
One other key query is which genes in these neurons are concerned in leptin’s means to cut back urge for food, Campbell says. “Now that we all know the particular cells on which leptin is performing, we are able to reply that query.”
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he discovery of BNC2 neurons is an element of a bigger effort to know how totally different mind circuits management feeding behaviors. In one other research printed in October, Friedman’s workforce found a three-neuron circuit within the mind that hyperlinks starvation indicators to chewing—a course of vital for consuming. The circuit, which entails hypothalamic neurons that specific brain-derived neurotrophic issue (BDNF), seems to manage the motion of the jaw muscle mass. Activating BDNF neurons in mice reduces each starvation and pleasure-driven consuming, whereas inhibiting them causes the animals to chew compulsively, even when no meals is current.
“Now we now have a circuit, and we are able to go from the neurons that sense the vitality state to the neurons that management the muscle mass,” says lead investigator Christin Kosse, a analysis affiliate in Friedman’s lab.
Each research from Friedman’s workforce spotlight the complexity of the mind circuits that management feeding conduct, says Richard Simerly, professor of molecular physiology and biophysics at Vanderbilt College, who was not concerned within the research. Starvation just isn’t an “on or off” state however a graded response formed by leptin and different inside indicators, in addition to exterior cues such because the presence of meals, he says. So a few of the findings might also assist neuroscientists perceive how the mind balances starvation with competing drives, comparable to thirst and ache.
BNC2 neurons combine indicators from each leptin and GLP-1 and will function key gamers in processing and balancing numerous kinds of info associated to feeding conduct, Campbell says. “Are [BNC2 neurons] simply carrying hormonal info to AGRP neurons, or are they relaying other forms of knowledge, like sensory info?” he says. “I believe this [work] raises a variety of actually thrilling questions, and we now know the place to search for the solutions.”
