Heady Stuff

New research on how fat influences brain neuronal activity

By Kate Yandell | November 1, 2015


Imagine yourself eating a juicy burger, topped with a perfectly melted slice of cheese and nestled in a soft bun. Your brain experiences a sweet spike in pleasurable chemicals as your teeth tear through the carbohydrate exterior and sink into the fatty, proteinaceous core.

Given humankind’s long history of struggling to find food, it makes sense that people are highly motivated to hunt it down, and that we experience intense pleasure when we finally eat it. “[If] you never know when you can have your next meal, then it really pays to have a few extra kilos on your [body],” says Lauri Nummenmaa, a neuroscientist at Aalto University in Finland. Our brains are still wired to seek nutrients “even though food and nutrition [are] omnipresent in Western society.”

But gustatory pleasure may actually be dulled in obese people, according to work Nummenmaa and his colleagues published earlier this year (J Neurosci, 35:3959-65, 2015). The researchers found that the brains of morbidly obese women contained fewer μ-opioid receptors available for binding than the brains of women of normal weight. These receptors allow people to feel the intense rushes of pleasure that come with activities from eating to using heroin.

While obesity or related changes lead to pathological neuronal activity, other new work indicates that a little body fat might be good for the brain.

“If there is insufficiency in [the food reward processing] system, the compensation would be to reach the pleasurable level [by eating] a little more,” explains Zdenka Pausova, a senior scientist at Toronto’s Hospital for Sick Children who was not involved in the study.

Nummenmaa speculates that, as people increase their caloric intake, their response to opioids lessens. Perhaps this spurs them to overeat even further, in hopes that the pleasurable sensations will return.

Nummenmaa and his colleagues infused 13 morbidly obese women and 14 women of healthy weight with radioactive tracer molecules that bound to either dopamine or μ-opioid receptors. The researchers then used positron emission tomography (PET) to scan the women’s brains, revealing a weight-dependent pattern: tracers bound to significantly fewer μ-opioid receptors in the brains of morbidly obese women than in the brains of women of healthy weight, particularly in brain areas involved in reward. The most straightforward explanation is that the number of μ-opioid receptors decreased in the morbidly obese women, Nummenmaa says. (The morbidly obese women had normal dopamine receptor availability.)

The finding “is consistent with addiction biology in general—where excess stimulation via addictive substance causes increased neurotransmitter secretion,” Catherine Carpenter, who studies public health at the University of California, Los Angeles, writes in an email to The Scientist.  “[The] number of neuroreceptors decrease[s] in response.”

“Where do these differences in brain receptor densities come from?” asks Nummenmaa. “Do they follow up people gaining weight, or are they . . . a risk factor for gaining weight?”

To begin to answer these questions, Nummenmaa’s team again imaged the availability of dopamine receptors and μ-opioid receptors, this time in the brains of 16 morbidly obese women who were planning to have bariatric surgery. They then imaged the same women’s receptors again six months after the procedure.

The μ-opioid receptors seemed to recover following the surgery—so much so that the researchers couldn’t distinguish between the opioid systems of the bariatric surgery patients and healthy people (Mol Psychiatry, doi:10.1038/mp.2015.153, 2015). Less certain is why bariatric surgery normalizes μ-opioid receptors. Of course, people who receive bariatric surgery tend to lose weight. The average weight loss of participants in the study exceeded 50 pounds by the time their μ-opioid receptors were measured following surgery. But these people were still technically above normal weight despite their weight loss, Nummenmaa notes.

Beyond simple weight loss, Nummenmaa hypothesizes that eating habits, which drastically change immediately following bariatric surgery, could influence the μ-opioid system. The researchers are now studying how natural opioid release corresponds to eating behavior.

The bariatric surgery findings indicate that obesity or related nutritional or metabolic states alter μ-opioid receptor availability. Other work shows how people’s μ-opioid receptor subtypes might influence susceptibility to obesity. A recent study by Pausova indicates that adolescents with one μ-opioid receptor variant eat relatively low levels of fat and tend to weigh less and have lower body fat than their peers (Mol Psychiatry, 19:63-68, 2014).

It may even be possible that lowered receptor availability in obesity stems from an overly responsive food-reward circuit, suggests Kent Berridge, a University of Michigan psychologist and neuroscientist who was not involved in Nummenmaa’s study. People with a hyperactive reward system get intense pleasure from food, and so they overeat to tap into those sensations, Berridge speculates. This overstimulation of their pleasure circuitry ultimately weakens it.

WEIGHING ON THE MIND: Adipose tissue may serve as a systemic NAD+ modulator, according to research conducted by biologist Shin-ichiro Imai of Washington University in St. Louis. The key enzyme driving effects seen in the hypothalamus is likely NAMPT (nicotinamide phosphoribosyltransferase).ILLUSTRATION BY KEI HAYASHIBut while obesity or related changes may lead to pathological neuronal activity, a little body fat might actually be good for the brain. Shin-ichiro Imai, a molecular biologist at Washington University in St. Louis, showed earlier this year that fat tissue in the bodies of mice releases an extracellular form of nicotinamide phosphoribosyltransferase (eNAMPT), an enzyme that travels to the hypothalamus, gives animals energy during fasting, and activates antiaging pathways (Cell Metab, 21:706-17, 2015).

“Your fat tissue is actually very important to keep the function of the control center of aging, which is the hypothalamus,” says Imai. “This really suggests a novel idea.”

Most tissues make NAMPT on their own, using it to catalyze basic energy-producing reactions in the cell. But fat cells also convert NAMPT into a highly active form and release it as eNAMPT in a circadian-related fashion, particularly during times of fasting. For many years, the role of eNAMPT has been mysterious and controversial.

Imai and his colleagues decided to test eNAMPT’s role by engineering mice so that they could not express NAMPT in their fat cells, thereby also preventing them from making eNAMPT. They then looked for effects on a number of other tissues. Because some form of NAMPT is necessary for the synthesis of NAD+, a critical coenzyme in energy metabolism and its circadian control, this metabolic compound is reduced wherever NAMPT is reduced. Sure enough, levels of NAD+ decreased in the hypothalamus in the engineered mice. This suggested that the hypothalamus depends on eNAMPT specifically from fat cells to maintain normal NAD+ levels. Additionally, during normal waking hours at night, the engineered mice were less active than usual, and activity of the anti-aging protein SIRT1 was also reduced.

“Extracellular NAMPT is important to maintain normal NAD+ biosynthesis remotely in the hypothalamus,” Imai says.

The researchers also applied eNAMPT to pieces of tissue dissected from the murine hypothalamus, showing that the enzyme increased the neuronal activity of the cells. And they also demonstrated that overexpressing NAMPT in adipose tissue of mice leads to animals with high levels of NAD+ in the hypothalamus and high energy at night.

Imai speculates that animals evolved this “novel intertissue communication mechanism” so that they would be spurred to find food in times of famine. When an animal is nutrient-deprived, it becomes sluggish. But release of eNAMPT from fat cells spurs it into action.

“It’s completely plausible, and the evidence looks pretty interesting in this paper, but definitely it’s the sort of thing that’s going to need some validation over time,” says Joseph Baur, who studies aging and metabolism at the University of Pennsylvania’s Perelman School of Medicine.

Today, food is much more abundant. But eNAMPT may exert an enduring positive influence by triggering the SIRT1 anti-aging pathway. This may be why some studies have shown that people live longest when they are very slightly overweight. (See “A Weighty Anomaly.")

Imai says that brain-fat interactions evolved for a valid purpose. The challenge is figuring out how to optimize them in our modern society, so that we can both prevent obesity-related pathology and preserve fat’s beneficial roles.

“Being slightly chubby is totally different from being morbidly obese,” writes Imai in an email. “Maybe a take-home message is that too much is always bad.”

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Avatar of: Rachel Francon

Rachel Francon

Posts: 3

November 19, 2015

A very interesting article. However, we would like to add an account of why things happen the way they seem. First the NADH process is a potentially inflammatory process mediated via the KYNURENINE Cycle which passes down through a synergistic participation of both Microglia and Astrocytes to lead to differential receptor production in selected neurons which are supported and supervised by these two cell types.

Secondly, the question is not, as we see it, the cells that are measured in the moment. But what has been happening with the arisal of new cells every minute of the day via stem cell like cells and pluripotent progenitors to immediate and differnetiated precursors.

We  tend tospeak of various facts "IN the cells" being changed...but what is likely happening via the Microglia and the Astrocytes is that certain cells are dying and certian new cells ( supervised in their birthing ..as differnetiation is needed....by Microglia) come on the scene.

We have a tendency to take two "snapshots" of the tissue at differentt moments , B and A, but do not note that in all likelihood the cells we view at time B are not the same cells we viewed at Time B, that change is constantly occurring behind the sceines. .And that what has happend is not a change "in state', but a change in the changing of that state.

 In truth  we know from the recent explosion in the knowledge of stem cells in each tissue, including the brain(and the progression of those pluripotent cells  to mobilization in the relevant areas of the brain that what is occurring between those two moments is the "coming on the scene" of new cells via the process of neurogenesis and the departure of old cells as well.

When measures are made at differnet points in times and locate differences in neurons at those two times,  the differences observeeed are NOT due to the changes in formation via "rewiring" of the same old neurons .  Rather the observed differencest are likelyresultant from entirely new neurons, with different reactivity and activity,  now on the scene via neurogenesis,  

The  differentiation and mobilization of precursor cells is everywhere between and behind the lines of the comments in your article. It is a crucial issue in all of medicine.  For example, the SIRT reference smacks of this as well.  All of logic and a lot of science points us to the former...newly differentiated cells being produced and replacing the old cells.

It should be noted that the mu opioid receptors have some interesting functions beyond beyond responsive and activatied by mu opioids They are also reactive to endocannabinoids, which are strongly implicated in neurogenesis mediated pattern separation by the brain. ...

Conseuently, with new cells participaing, we can then see the formation of new behavior patterns.

These changes in behavior are likely related to an alteration in the reward system.///amd ..most likely related to the insular cortex  (as they mention in the abstract for this research) where   "salience" of states is weighed and acted upon..The involvement of the insula tin this process, and its change in activity between Time B and Time A,  suggests that the behavior patterns are restructured with differential patterns of conncecitivty between the default mode and executive action networks arising.

The salience network generating "rewards" upwardly, as a result of the neurogeneis and the altered connectivity through differential contact with DMN network cells and limbic system cels with the hippocampus is undoubtedly the "link" between these events and those new cells produced in the SVZ and migrating to  the hippocampal and hypothalamic areas.as we conjecture here,  that have been brought into play between times B and A.

Variatons in the anterior insula functioning are known to result in alteration in hypocretin neuron innervation in the reward centers of the brain that in turns  determine the impact on behavior of the "salience" of felt states accessed through the insula.

It is likely that ese differential patterns of functional connectivity, mediated by the insula,  depend in teurn  on the work of the glial and microglial cells (the latter in particular), since they are also in direct communication with other  immune cells in the gut and elsewhere in the body, including T cells, which are now understood to play essential roles in cognitive functioning in the brain,....and which pass through the blood brain barrier to communicate with the microglia.

 That the patterning of functional connectivity networks, the Default Mode Network and the Executive Action or Task Network are also related to glial cell functioning, helps us tie the altered connectivity andthe  altered feedback loop between reward and state to the neurogenesis of which we speak.

The life and death of various cells in each tissue of the body are also regulated by those very macrophage like cells in each tissue, and, in particular, the microglia in the brain and the astrocytes with which they work synergistically to enact apoptosis and the mobilization and final differentiation of immediate precursor neural cells.

This brings us back full circle to the Kynurenine cycle, whereby NADH is modulated and whereby, at the same time, receptors on various neurons are differently produced and modulated via the synergistic interaction of the microglia and the astrocytes and the various enzymes each of them contributes to the Kynurenine pathway and the "forks " on the way to its completion.

I am currently preparing a "journalistic style" paper of the sort Scientist does on the general implications of this topic for specific problems in various tissues . .   Would be glad to share it here? 

The change focus as theorization in sciience becomes refined and new paradigms emerge, which we advocate here, is a change in perspective which leads  to  better understanding of what happens in a system between any two times, B and A and how to tie changes in observation to those changes in "state" was most clearly first enacted in Newton's revolutionary paradigm many hundreds of years ago.  The same change  arises in many other scientific areas as paradigms shift..


Rachel Francon



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