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A key discovery finds nutrient molecules that send messages to the brain

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A certain type of G-protein coupled receptor inside the intestine senses the types of nutrients found in food passing through it. The receptor relays the information to the brain and the immune system, helping to regulate food intake and insulin production. Greg Aponte's research with these receptors could potentially help treat obesity and diabetes.


Hamburger doesn't rank high on most health food lists. But chances are, a juicy bite of burger will do your body more good than simply fueling your cells. Since the 1920s, scientists have speculated that there is a sensory system that specifically detects the mere presence of fats, proteins, and other nutrients in the gut. Now, UC Berkeley Professor of Nutritional Sciences Greg Aponte has discovered a certain class of molecules that can act as intestinal sentinels. They respond to the presence of nutrients in the gut by sending a barrage of messages to the brain, immune system, and other body cells.

Aponte's got his office-cum-laboratory equipped with a functional kitchen for his own use. A wall of herbal tea boxes lines one counter, while a mini-refrigerator, bottled water, and a microwave take up another corner. He acknowledges the collection with an apologetic smile. "We practically live here sometimes, so it's good to have a few food supplies around."

Whatever it is Aponte consumes, it's kept him both trim and energetic. He explains that studying how the presence of foods affects the body helped him uncover a mechanism for an intestinal awareness system. "We traditionally think of nutrients as things that get absorbed. But there can be a lot of factors in nutrients that might affect your health and genetic response that don't get absorbed," Aponte says. "We've been interested in ways that nutrients can act as signal molecules, not as metabolic substrates."

Aponte has been working with a widespread class of cell receptors called G-protein coupled receptors, or GPCRs. Found in the tongue, the eye, the nose, and the nervous system, these proteins are heavily involved in environmental sensing through taste, smell, and vision, as well as depression, euphoria, and pain control.

A GPCR in-situ bears an uncanny resemblance to that famed but bogus photo of Nessie the Loch Ness Monster.

Because they open doorways into so many body systems, GPCRs are prime targets for drugs. Up to 40 percent of all pharmaceuticals interact with these proteins, adding up to a $60 to $80 billion-dollar-a-year business.

In the body, GPCRs bob about in the sea of fatty molecules that make up cell membranes. In structure, they consist of six sinuous bends plus a head and a tail that protrude above and below the surface of this sea; a GPCR in-situ bears an uncanny resemblance to that famed but bogus photo of Nessie the Loch Ness Monster.

This serpentine structure endows GPCRs with multiple talents. The bends, head, and tail can serve as docking sites for molecules floating inside and outside the cell, allowing each GPCR to bind to several molecules at once. Some GPCRs are even promiscuous, able and willing to bind to more than one type of activating molecule.

"You can get one molecule that turns it on, another that may bind elsewhere to modify that signal, and on and on. Inside the cell, it may be coupled to other molecules that themselves can be modified," Aponte says. "What you have is a rheostat: instead of a simple on and off switch, you are able to attenuate this receptor by degrees."

As if they weren't versatile enough, GPCRs have been found to bind many different kinds of compounds, from lipids to sugars, proteins to steroids. Because foods are also made up of a wide range of compounds, "it seemed logical that they might be involved in sensing what's in the intestine," says Aponte.

Aponte began his search for a likely sensor among "orphan" GPCRs-receptors with unknown activating molecules. What he needed was an orphan that was found in both the central nervous system and the lining of the intestine. Among the qualifiers was a receptor called GPR93. It studded intestinal cells on two sides-the surface exposed to food, and the surface exposed to blood. This finding suggested the receptor not only could be involved in transmitting dietary signals between the gut and brain, but also to other parts of the body via the circulatory system.

Aponte then needed to find a molecule that triggered GPR93. He added one nutrient after another to cultured intestinal cells with the receptor. Broken bits of protein molecules did the trick, causing cells with GPR93 to turn "on" by releasing a burst of calcium ions.

"It is the first time a GPCR has been shown to sense dietary protein in the interior of the intestine," Aponte says. "That means there are also a lot of other intestinal receptors out there" waiting to find their nutrient activators. Recently, other researchers have discovered taste receptors in intestinal cells. Because many toxins are also bitter, the gut version of this receptor could be serving as a protection mechanism by signaling the intestine to expel food.

Already, Aponte has determined that GPR93 turns on genes that affect the immune system, cause cells to multiply and mature, and modify digestion. "If these GPCRs can be activated by macromolecules from nutrients, they could also be sensing bacteria or components of bacteria," Aponte says. A direct connection between the digestive system and the immune system isn't far-fetched; an estimated 70 percent of the immune system is located in and around the gut.

A direct connection between the digestive system and the immune system isn’t far-fetched; an estimated 70 percent of the immune system is located in and around the gut.

"We also know it's in the nerves producing signals in the central nervous system. It could be a way of sensing energy intake outside of metabolism, which in turn could affect appetite," Aponte says. "So one of the challenges is to see if those receptors can literally sense what's in the intestine and give a signal directly to the brain." In addition, Aponte's group has shown that triggering GPR93 stimulates hormones that regulate food intake and affect insulin, suggesting that it could provide a means to treat those who are obese or diabetic.

Aponte has begun characterizing in detail the molecular lock and key that allows protein to bind to the receptor. This information could streamline the development of better pharmaconutrients. Understanding how nutrients interact with this intestinal sensory system could lead to dietary additives designed specifically to turn on gut receptors rather than be absorbed.

One population that could benefit are patients who must take all of their nutrition intravenously. Left empty for long periods of time, their intestines can deteriorate and eventually stop functioning. These patients also tend to get more infections, show an increased inflammatory response and face a greater risk of organ failure. Triggering the intestinal GPCRs of these patients with nutrients that aren't absorbed could help maintain their health without irritating the gut.

For the rest of us, such pharmaconutrients have the potential to boost immune system strength and maintain overall health. And that's good news for anyone who wants to keep enjoying hamburgers for many years to come.

-Kathleen Wong is a biologist and
freelance science reporter, and a writer for UC Berkeley’s Science Matters


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Inside the small intestine, GPCRs (shown here in green) bob about in the sea of fatty molecules that make up cell membranes. Inset: The bends, head, and tail of the GPCR can serve as docking sites for floating molecules, such as the dietary proteins shown moving towards the cell. In the case of GPR93, broken bits of protein molecules caused GPR93 to "turn on" and release calcium ions (shown in yellow) inside the cell.

Nicolle Rager Fuller specializes in science illustration and information design.