Study shows that low body fat percentage is not good for the brain.


An enzyme secreted by the body’s fat tissue controls energy levels in the brain, according to new research from Washington University School. The data findings, in mice, underscore a role for the body’s fat tissue in controlling the brain’s response to food scarcity, and suggest there is an optimal amount of body fat for maximizing health and longevity.  The opensource study appears in the journal Cell Metabolism.

The team showed that fat tissue controls brain function in a really interesting way.  The results suggest that there is an optimal amount of fat tissue that maximizes the function of the control center of aging and longevity in the brain. The researchers note that it is still unclear what that amount is or how it might vary by individual. However, in mice it was shown know that if they don’t have enough of a key enzyme produced by fat, an important part of the brain can’t maintain its energy levels.

The team hypothesize that the findings may help explain previous studies that show a survival benefit to having a body mass index toward the low end of what is considered overweight.  The researchers state that as humans age, people who are slightly overweight tend to have fewer problems.  In the past the medical community was unclear as to why people categorized as being slightly overweight tend to have a lower mortality rate. However, the study suggests that if a person doesn’t have an optimal amount of fat, then that person is affecting a part of the brain that is particularly important for controlling metabolism and aging.

Previous studies from the team demonstrated the importance of an enzyme called NAMPT in producing a vital cellular fuel called NAD. Traditionally, NAMPT is thought to be important for making this fuel inside cells. However, the team noticed that fat tissue churned out a lot of NAMPT that ended up outside cells, circulating in the bloodstream.  The team state that there’s been a lot of controversy in the field about whether extracellular NAMPT has any function in the body, adding that some researchers theorise that it’s just a result of leakage from dead cells. However, the team’s data indicates that it is a highly active enzyme that is highly regulated and such fine-tuned regulation suggests secreted NAMPT is doing something important somewhere in the body.

To find out what that is, the researchers raised mice that lacked the ability to produce NAMPT only in the fat tissue.  They were not surprised to see that energy levels in the fat tissue plummeted when fat tissue lacked this key enzyme.  Other tissues such as the liver and muscles were unaffected. But there was one distant location that was affected, and that was the hypothalamus.  The team state that the hypothalamus is a part of the brain known to have important roles in maintaining the body’s physiology, including regulating body temperature, sleep cycles, heart rate, blood pressure, thirst and appetite. Mice with low NAMPT in fat tissue had low fuel levels in the hypothalamus. These mice also showed lower measures of physical activity than mice without this defect in the current study.

The data findings suggest that fat tissue communicates specifically with the hypothalamus, influencing the way the brain controls the body’s physiologic set points. Indeed, past work from the group also supported an important role for the hypothalamus in whole body metabolism. They showed that increasing the expression of a protein called SIRT1 in the mouse hypothalamus increased the mouse lifespan, mimicking the effects of a calorie-restricted diet.  The researchers suspect that all these processes influence one another. Their past work on the hypothalamus has also shown that SIRT1 function is dependent on energy levels in cells. And the new study links energy levels in the hypothalamus to the fat tissue’s newly identified function.

After examining what happens to mice with fat tissue that doesn’t make NAMPT, the researchers performed the opposite experiment, studying mice that produced more NAMPT in fat tissue than is typical.  Mice that expressed high levels of NAMPT in the fat tissue were very physically active. Their activity levels were especially pronounced after fasting. The mice with low NAMPT in the fat tissue became even more lethargic after the fasting period. The mice with an overabundance of NAMPT in the fat tissue appeared unaffected by the period of time without food, remaining at activity levels similar to normal mice without food restriction. In fact, the mice with a lot of NAMPT produced in their fat behaved very similarly to the mice with a lot of SIRT1 in the brain.

The team are now studying whether an overabundance of NAMPT in the fat increases lifespan, as they showed in the mice with an overabundance of SIRT1 in the brain.

The researchers also found they could temporarily boost the physical activity of the mice with low NAMPT in the fat tissue by injecting NMN, the compound that the enzyme NAMPT produces. Imai is investigating NMN as a possible intervention in diseases associated with aging.  The team speculated that this NAMPT signal from the fat tissue, especially in response to fasting, may serve as a survival mechanism.

The team surmise that this phenomenon makes sense in the wild, adding that if a person can’t get food and they just sit around and wait, they won’t survive. So the brain, working in conjunction with the fat tissue, has a way to kick in and let the person move to survive, even when food is scarce.

Source:  Washington University School of Medicine

 

Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD+ biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD+-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD+/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD+ production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD+, SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD+ biosynthesis at a systemic level.  SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice.  Lmai et al 2015.

Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD+ biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD+-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD+/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD+ production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD+, SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD+ biosynthesis at a systemic level. SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. Lmai et al 2015.

 

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