MC4R 'Hunger Switch' May Be Good Target for Anti-Obesity Research

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Researchers have identified a melanocortin 4 receptor (MC4R) that controls hunger, a discovery that could have implications for the development of anti-obesity drugs.

Bradford Lowell, MD, PhD, of Beth Israel Deaconess and Harvard Medical School, and colleagues, had previously shown that agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons at the base of the hypothalamus are oppositely regulated by caloric depletion to affect appetite; AgRP react during fasting to cause feelings of intense hunger, while POMC neurons promote satiety. The paraventricular nucleus of the hypothalamus (PVH) is both the main site of the MC4R and site of outflow of ARCAgRP neurons.

The researchers utilized Cre-recombinase knockout mice and DREADD technology to selectively control PVH MC4R neuron activity. When they turned off the PVH MC4R cells in well-fed mice, the mice consumed food uncontrollably despite having no caloric need for it. Alternately, when the researchers activated the PVH MC4R neurons in unfed mice, the mice did not eat.

Using a tracer molecule to further visualize cell activity, the researchers were able to identify dense innervations of the lateral parabrachial nucleus (LPBN). Through optogenetics, researchers then confirmed that activation of the PVH MC4R-LPBN circuit was associated with a reduction in food consumption.

In a final test of two hunger and food intake hypotheses — reward vs. drive reduction — researchers exposed unfed genetically-modified mice and normal mice to laser activation of the PVH MC4R-LPBN circuit in a two-room compartment, one room where the circuit was turned on and off in another. Normal mice showed no preference for either room; however the unfed genetically-modified mice showed a preference for the blue laser light chamber that stimulated satiety. Well-fed mice, on the other hand, seemed unaffected by the laser light activation and showed no preference for it.

The researchers concluded that the PVH MC4R-LPBN circuit promotes physiological satiety and encodes positive emotional valence, indicating that the circuit could be a promising target for anti-obesity drugs. 

MC4R 'Hunger Switch' May Be Good Target for Anti-Obesity Research

Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH).

Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVHMC4R neurons and further identify these cells as a functional exponent of ARCAgRP neuron–driven hunger.

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