A switch that occurs in neurons within the hypothalamus could explain the body’s tendency to maintain higher, undesirable weight levels, rather than an ideal weight, according to new research. The switch involves receptors that trigger or inhibit the release of the orexin A peptide, which stimulates the appetite, among other behaviors.

The team of American and Italian neuroscientists found that in normal-weight mice, activation of this receptor decreases orexin A release. In obese mice, activation of this receptor stimulates orexin A release.

“The striking finding is that you have a massive shift of receptors from one set of nerve endings impinging on these neurons to another set,” says Ken Mackie, M.D., professor in the department of psychological and brain sciences in the College of Arts and Sciences at Indiana University Bloomington. “Before, activating this receptor inhibited the secretion of orexin; now it promotes it. This identifies potential targets where an intervention could influence obesity.” Dr. Mackie’s team at the Gill Center for Biomolecular Science at IU Bloomington collaborates with Vincenzo Di Marzo, Ph.D.’s team at the Institute of Biomolecular Chemistry in Pozzuoli, Italy.

Both teams study the endocannabinoid system, which is composed of receptors and signaling chemicals that occur naturally in the brain and have similarities to the active ingredients in marijuana. This neurochemical system is involved in a variety of physiological processes including appetite, pain, mood, stress responses, and memory.

Food consumption is controlled in part by the hypothalamus but also by multiple neurochemical systems, including the endocannabinoid system, representing what Dr. Mackie describes as a “balance of a very fine web of regulatory networks.”

An emerging idea, he says, is that this network is reset during obesity so that food consumption matches maintenance of current weight, not a person’s ideal weight. Thus, an obese individual who loses weight finds it difficult to keep the weight off, as the brain signals the body to eat more in an attempt to return to the heavier weight.

The study found that in obese mice, CB1 cannabinoid receptors become enriched on the nerve terminals that normally inhibit orexin neuron activity, and the orexin neurons produce more of the endocannabinoids to activate these receptors. Activating these CB1 receptors decreases inhibition of the orexin neurons, increasing orexin A release and food consumption.

“This study identifies a mechanism for the body’s ongoing tendency to return to the heavier weight,” Dr. Mackie says.

The researchers conducted several experiments with mice to understand how this change takes place. They uncovered a role of leptin, a key hormone made by fat cells that influences metabolism, hunger, and food consumption. Obesity causes leptin levels to be chronically high, making brain cells less sensitive to its actions, which contributes to the molecular switch that leads to the overproduction of orexin.

The findings were published in the Proceedings of the National Academy of Sciences Early Edition this week, in a paper titled “Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons”.

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