Nevertheless, your brain will be keeping tabs directly, suggests a report in the November 26th issue of the journal Cell, a Cell Press publication.

Researchers have discovered in studies of rats that one type of lipid produced in the gut rises after eating fatty foods. Those so called N-acylphosphatidylethanolamines or NAPEs enter the bloodstream and go straight to the brain, where they concentrate in a brain region that controls food intake and energy expenditure.

The good news is that the most abundant form of NAPE doesn't seem to lose its effectiveness even when it is artificially administered over the course of several days. That means treatments designed to boost NAPE levels might offer a new way to fight obesity.

"A lot of gut hormones have an effect on food, but when you give them chronically they lose their effectiveness," said Gerald Shulman of Yale University School of Medicine. Or, for instance, another nutrient-sensing, gut-derived peptide known as CCK leads animals and people to eat smaller meals, but they eat them more often, yielding no change in the overall calories consumed, he said.

"Here, we gave rats NAPE for five days and saw a continuous reduction in food intake and a decline in body weight," Shulman said. "It suggests NAPE or long-acting NAPE analogs may treat obesity." For that, however, much work remains to extend the new findings in rats to humans, he added.

The researchers focused in on NAPEs potential role as a fat intake signal after screening the blood for lipids that rise after a high-fat feeding. Among the increased metabolites was a class of phospholipids, the NAPEs, of previously unknown physiologic function in plasma.

Now, they show that NAPEs are secreted into circulation from the small intestine in response to ingested fat and that systemic administration of the most abundant circulating NAPE, at doses naturally found in the bloodstream, lowers food consumption in rats without making food unappealing to the animals.

By injecting radiolabeled NAPE into the animals, they found that the lipid enters the brain and is particularly concentrated in the hypothalamus. Infusions of NAPE directly into the brain also led the animals to cut back on calories, supporting the notion that its effects may be mediated through direct interactions with the central nervous system. Curiously, they also found that NAPE left the animals in what is sometimes described as a food coma.

Animals fed a high-fat diet for 35 days lose the normal increases in circulating NAPE after a fatty meal. That suggest that derangements in NAPE secretion associated with chronic high-fat feeding may contribute to diet-induced obesity precipitated by overexposure to triglyceride-rich foods. However, those animals still responded to NAPE treatment.

"These results suggest that chronic C16:0 NAPE treatment is capable of generating a state of negative energy balance over multiple days and merits longer-term studies in rodents and nonhuman primates to examine its potential for treatment and prevention of diet-induced obesity," the researchers wrote. "In conclusion, these data support the hypothesis that circulating NAPEs, synthesized in the small intestine from ingested fat, may be part of an important physiologic negative feedback loop that serves to reduce food intake and arousal after a fat-containing meal."

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When the researchers delivered tiny amounts of NAPE directly into the brain, it had the same effect as a larger dose delivered to the blood. This suggests that the compound communicates directly with the brain, Shulman says.

Indeed, they found that NAPE injected into the blood did cross the blood-brain barrier and was concentrated in the hypothalamus, a specific region of the brain that governs hunger. There, they found that NAPE calmed neurons that stimulate appetite. The team made those conclusions after inspecting brain samples that had been stained to reveal the cells in which NAPE was active. "Most appetite regulation is hypothalamic, so we were excited that [NAPE] was working centrally," Shulman says. "That suggests [NAPE] is involved in the gut-brain axis. It's a way the gut communicates to the brain that there's energy coming in and you need to shut down food intake."

The team next wanted to know if NAPE would stay effective with longer-term treatment, so they outfitted 22 rats with vests that allowed them to move freely in their cages while they hooked up to an IV that dispensed NAPE. The vests permitted the rats to eat, sleep, and rest while still receiving infusions of NAPE. Over five days, control rats continued to gain weight normally, but NAPE-treated rats ate less and lost ten percent of their body weight-while appearing otherwise well and healthy.

Shulman and his team are now monitoring NAPE levels in humans, to see if they rise after a meal the same way they do in rodents. They also plan to test NAPE for effects on appetite in non-human primates. If these studies parallel the results they have observed in mice and rats, Shulman says, a clinical trial with NAPE or NAPE-like compounds may be on the horizon.

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