Summary: Researchers have identified a molecular mechanism that controls feeding behavior in mice by adjusting the electrical activity of a few thousand neurons.
Source: Baylor College of Medicine.
Researchers from Baylor College of Medicine, South China Agricultural University, the University of Texas Southwestern Medical Center at Dallas and the University of Texas Health Science Center at Houston have identified a key mechanism that regulates feeding behavior in mice by modulating the electrical activity of a specific group of brain cells. Their findings were published in Cell Reports.
“This work explains why mice initiate feeding when they are hungry and stop when they are full,” said senior author Dr. Yong Xu, associate professor of pediatrics at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital and of molecular and cellular biology at Baylor. “We focused on a relatively small population of neurons called AgRP/NPY neurons in the hypothalamus. These neurons are essential: when they are absent, mice stop eating and die within days.”
The electrical firing of AgRP/NPY neurons is closely tied to the animal’s nutritional status. When a mouse is hungry, these neurons become more active; when the mouse is satiated, their activity falls. Changes in neuronal firing trigger corresponding behaviors: increased firing prompts the mouse to search for food and reduces anxiety and aggression, promoting foraging and feeding. Reduced firing, which occurs after feeding, suppresses food-seeking behaviors. This cycle repeats as the animal alternates between hunger and satiety.
Xu and his team investigated the molecular basis that switches AgRP/NPY neurons between these active and inactive states.
The hunger/satiety switch
“We discovered that the expression of a protein called SK3 shifts dramatically in AgRP/NPY neurons depending on nutritional state,” Xu explained. “In well-fed animals, nearly all AgRP/NPY neurons express high levels of SK3. After fasting, SK3 levels drop substantially. This change appears to be specific to this neuronal population.”
SK3 is a small-conductance calcium-activated potassium channel that helps move potassium ions out of the cell. The researchers showed that SK3 levels directly influence neuronal excitability.
“When SK3 levels are low during fasting, less potassium leaves the neurons, which increases their firing and drives food-seeking behavior,” Xu said. “When the animal is satiated and SK3 is abundant, potassium efflux increases, reducing neuronal firing and suppressing appetite.”
To confirm SK3’s role, the team created mouse models lacking the Sk3 gene specifically in AgRP/NPY neurons. “Without SK3, the hunger/satiety switch is lost: AgRP/NPY neurons remain hyperactive, the animals overeat and become obese,” Xu reported. These results indicate that SK3-mediated potassium currents are a critical intrinsic brake on these neurons when animals are fed.
The study links a single molecular player to broad behavioral and metabolic outcomes. By showing that SK3 levels change with feeding state and that SK3 deletion leads to persistent neuronal activity, hyperphagia and weight gain, the research identifies SK3 as a central mediator that coordinates internal energy status with neural activity and whole-body energy balance.
Xu and collaborators suggest these findings could improve our understanding of human feeding disorders. “Our work opens the possibility of developing therapies that target SK3 to treat obesity and eating disorders,” Xu said, while noting further research is needed to translate these results from mice to humans.
Other contributors to the study include Yanlin He, Gang Shu, Yongjie Yang, Pingwen Xu, Yan Xia, Chunmei Wang, Kenji Saito, Antentor Hinton Jr., Xiaofeng Yan, Chen Liu, Qi Wu and Qingchun Tong.
Funding: The work was supported by grants from the National Institutes of Health, the American Diabetes Association, the American Heart Association and the Davis Foundation.
Original Research: The study titled “A Small Potassium Current in AgRP/NPY Neurons Regulates Feeding Behavior and Energy Metabolism” reports that SK3 in AgRP/NPY neurons is a key intrinsic regulator linking nutritional state to neuronal activity, feeding behavior and energy metabolism.
A Small Potassium Current in AgRP/NPY Neurons Regulates Feeding Behavior and Energy Metabolism
Highlights
• Fasting dramatically reduces SK3 expression in AgRP/NPY neurons
• Loss or mutation of SK3 in these neurons increases their activity in the fed state
• SK3 mutation in AgRP/NPY neurons enhances susceptibility to diet-induced obesity
• SK3 mutation leads to excessive eating (hyperphagia) and reduced energy expenditure
Summary
AgRP/NPY neurons are essential for normal feeding behavior. Their firing rates are dynamically regulated by energy status and in turn coordinate feeding to meet nutritional demands. This study found that satiated mice express high levels of SK3, and SK3-mediated potassium currents inhibit AgRP/NPY neuronal activity. Food deprivation suppresses SK3, reducing those currents and facilitating fasting-induced neuronal activation. Targeted mutation of SK3 in AgRP/NPY neurons causes chronic hyperphagia, lowered energy expenditure and increased susceptibility to diet-induced obesity. These results identify SK3 as an intrinsic mediator that links nutritional status to AgRP/NPY neural activity and whole-animal energy balance.