CD38 links obesity, bacterial-induced inflammation, and reductive stress

The idea of this series is that the underlying condition that drives obesity forward is reductive stress, as defined by the NAD+/NADH ratio being too low (not enough NAD+).  CD38 is a membrane bound enzyme, expressed in most tissues, that increases throughout life, steadily reducing NAD+ levels​1​.  It is the body’s “primary NADase”, the main enzyme that is stealing from the NAD+ pool.  Along with dropping NAD+ comes decreased mitochondrial function and lowered metabolic rate. 

In past articles we’ve seen that the MAIN way we lose NAD+ is by converting it to NADH when it takes on an electron from our food.  When NADH pushes that electron onto Complex I of the mitochondrial electron transport chain, the NADH converts back to NAD+.

CD38 and other NADase are different.  They actually release the nicotinamide part of the NAD+, requiring another enzyme called NAMPT to regenerate NAD+ through the “salvage pathway”.  So there is a battle between CD38 and NAMPT to maintain NAD+ levels.  When CD38 activity levels are high, NAD+ levels go down.  Here is the whole pathway.  NR is nicotinamide riboside, AKA niagen. 

Mitochondria from cells lacking CD38 have very high levels of NAD+ and very high metabolic rates.  Conversely, mitochondria from cells where CD38 is overexpressed have low levels of NAD+ and low metabolic rates.

Mitochondria lacking CD38 have lots of NAD+.
Mitochondria lacking CD38 maintain high metabolic rate throughout life.

Mice lacking CD38 don’t get fat

The REALLY interesting thing about CD38 is that if you remove the CD38 gene from mice, they are totally resistant to high-fat diet induced obesity!​2​

I added the daily caloric consumption to each group of mice on their back in violet.  Which mouse over ate?  The one who gorged on 16.7 calories per day and remained lean or the one who restricted itself to 13.4 calories per day and got fat?  In addition to being gluttonous, the mice lacking CD38 were also lazy, showing much less spontaneous movement than normal mice.  So the lean mice lacking CD38 maintained its waistline via an eat-more-move-less strategy.

It looks like mice who don’t get reductive stress don’t get fat!

LPS induced CD38 induction links inflammation and obesity and is reversed by restoring NAD+

There has been lots of discussion about obesity being caused by gut bacteria and its associated inflammation.  It turns out that lipopolysaccharide (LPS), a compound released by bacteria into the bloodstream which stimulates the inflammatory response, upregulates CD38​3​.  You can make mice fat on a low fat, “chow” type lab diet that normally keeps mice thin by injecting them with LPS.​4​  Unfortunately this paper doesn’t follow the causality of LPS induced obesity all the way down to the NAD+/NADH level.

Endotoxin levels of LPS injected or diet-induced obese mice…
… correlate pretty nicely with fat stores.

This one does, though!​5​  It  is a very nicely done 2021 paper which clearly shows how LPS induces inflammation via upregulation of CD38 and a decline in NAD+.  The paper goes on to show that supplements which can restore NAD+ can reduce the LPS-caused inflammation.  

Mice were injected with LPS straight into their brains, which increased CD38 in the hippocampus and caused reductive stress and inflammation.  Mice were given either nicotimamide riboside (NR) or a flavone CD38 inhibitor called apigenin.  Both apigenin and NR increased the NAD+ levels and reduced inflammation as determined by levels of cytokines such as IL-6.  The inflammatory response to LPS is mediated in large part by CD38 induced reductive stress.

Injected LPS led to robust upregulation of CD38 in the hippocampus.
LPS (white bars) reduced NAD+ levels, which were restored by apigenin or NR.
The inflammatory marker IL-6 was reduced in response to Apigenin (yellow) or NR (blue) in the mice injected with LPS.

ALA as a double check

I introduced alpha lipoic acid (ALA) in the last article not only because it is interesting as a supplement but because it also is useful to confirm our understanding of how this all works.  ALA works primarily as an oxidant by oxidizing NADH and increasing the amount of NAD+.  With that in mind, ALA should ALSO reverse the effects of LPS induced inflammation.  It does.  This paper​6​ concludes, “ ALA inhibits LPS-induced monocyte activation and acute inflammatory responses in vitro and in vivo”.

Restoring NAD+

I’ve shown evidence that three different approaches to raising NAD+ levels are effective in combating LPS-induced inflammation.  

  1. ALA restores NAD+ via the direct oxidation of NADH.  
  2. Nicotinamide Riboside (AKA Niagen) provides an NAD+ precursor which gets around the bottleneck of NAMPT activity.
  3. Apigenin inhibits CD38, the primary thief of NAD+.

I believe in thinking about these problems from a pathway perspective.  Perhaps ALA will do you little good if your CD38 activity is high.  It may make some sense to take these together.

Summary

CD38 is the primary enzyme which is stealing your NAD+, putting you into reductive stress.  CD38 is greatly increased in response to the bacterial endotoxin LPS.  LPS is far from the ONLY thing that increases CD38, lots more of those to come!  LPS does, however, fill in one puzzle piece for us, “What is the link between LPS and obesity?”

In this series I’ve already written that reductive stress is the root cause of obesity and now we see how bacterial endotoxin can cause it.  The reason the last two articles (this and the previous one) were released in this order is that I wanted to explain the roles of alpha lipoic acid (ACA) and CD38.  Now that that is done, we can go ahead and start talking about how vegetable oil leads to reductive stresss….. 

Check back in!

  1. 1.
    Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metabolism. Published online June 2016:1127-1139. doi:10.1016/j.cmet.2016.05.006
  2. 2.
    Barbosa MTP, Soares SM, Novak CM, et al. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet‐induced obesity. FASEB j. Published online June 21, 2007:3629-3639. doi:10.1096/fj.07-8290com
  3. 3.
    Amici SA, Young NA, Narvaez-Miranda J, et al. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front Immunol. Published online July 10, 2018. doi:10.3389/fimmu.2018.01593
  4. 4.
    Cani PD, Amar J, Iglesias MA, et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes. Published online July 1, 2007:1761-1772. doi:10.2337/db06-1491
  5. 5.
    Roboon J, Hattori T, Ishii H, et al. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide‐induced microglial and astrocytic neuroinflammation by increasing NAD            +. J Neurochem. Published online May 9, 2021:311-327. doi:10.1111/jnc.15367
  6. 6.
    Zhang WJ, Wei H, Hagen T, Frei B. α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci USA. Published online March 6, 2007:4077-4082. doi:10.1073/pnas.0700305104
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