Blocking Inflammation is Like Choking the Fire: Long Term Weight-, Visceral- and Android-Fat Gain in Human Study Emphasizes Essential Role of TNF-α in Metabolic Control

Can cooling down the inflammation make your belly grow!?

(Mito-)Hormesis and the important and beneficial role of "inflammatory" cytokines, molecules etc. are one of my favorite topics. It's simply intriguing that health, performance and longevity apparently depend on the presence of a healthy amount (whatever that may be) of inflammation. Even the provision of low dose arsenic does not - as you may expect - shorten, but prolong the lifespan of several common model organisms (Schmeisser. 2013).

Findings like these don't just conflict with common sense, they are also in opposition to the still prominent free radical theory of aging and it's central message: Oxidation and inflammation are bad for you! No matter what! 

Too little is just as bad as too much

Most of you will remember one of my previous articles on (mito-)hormesis - if if that's not the case, I'd recommend you start with the "Inflammation is a True Fat Burner" article (read it!), because it (a) contains a lot of links and references to previous articles and (b) discusses a topic that is directly related to the study at hand. Whence you've refreshed your memories, you should actually be able to tell that it may not be a total idiotic undertaking to  ...

"[...] evaluate the long-term consequences of TNFα-inhibitors on body composition, especially on the android/visceral region, in patients with RA [rheumatoid arthritis] or AS [ankylosing spondylitis]." (Toussirot. 2013)

Ok, rheumatoid arthritis and ankylosing spondylitis, that's not you. I understand that, but it's neither a rodent nor a nematode study and despite the fact that the patients in the study suffer from chronic inflammation the data Toussirot et al. collected can provide us with a glimpse on what could happen to any of us, if we subscribe to the "the-less-inflammation-the-better" hypothesis and consume high amounts of drugs or natural substances to suppress cachexin (aka TNF-alpha), of which the corresponding Wikepedia entry tells you that it is "an adipokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction." (wikipedia)

Figure 1: Markers of inflammation, health and joint function after 24 months treatment in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients (Toussirot. 2013)

As you can see both, the provision of a TNF-alpha blocker lead to significant reductions in inflammation (CRP ↓) in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients (Figure 1, ESR + CRP). The overall reduction in non-specific inflammation (assessed by ESR), on the other hand, reached significance only in the patients with "classic" rheumotoid arthritis - for our purpose, i.e. drawing inferences with respect to our situtation, this difference is not that relevant. What is relevant the total annihilation of C-reactive protein (CRP), an acute phase protein which is elevate immediately after a strenuous workout - just like IL-6, by the way (see "IL-6 True Muscle Builder or Just a Measure of Workout intensity?" | read more).

Weight gain right due to the absence of inflammation?!

Contrary to the previous post on IL-6 we are not dealing with muscle hypertrophy, here. The thing that's growing is the belly - the android fat mass, visceral fat and total BMI of the study participants in both groups and and additional significant increase in total (subcutaneous + visceral) fat mass in the ankylosing spondylitis patients (see Figure 2).

Figure 2: Changes in body composition after 24 months (Toussirot. 2013)

Said increase in total fat mass was significant (p=0.02) and came hand in hand with a gain in total body weight. It is thus not surprising that the scientists found ...

"[...] a significant increase inbody weight (+1.9 %; p=0.003), body mass index (+2.5 %; p=0.004), total fat mass (+11.1 %; p=0.007), and fat in the android region (+18.3 %; p=0.02) [...]" (Toussirot. 2013)

... when they calculated the mean changes in body composition for both groups. In this context, it's probably worth mentioning that the success of a few outliers who managed to keep the visceral fat off, masquerades the "substantial, albeit nonsignificant" (Toussirot. 2013) +24.3%  increases in visceral fat and thus diabetes and cardiovascular disease risk among the rest of the study participants.

Bottom line: While I do hope that you don't have to take a TNF-α inhibitor to make it through the day, the general messages of this paper are still relevant for all everyone - even, or maybe especially for the for the healthiest of us:

Human study: Antioxidant supps hamper "gains" in elderly individuals, as well. Get all the details → here!

• The total annihilation of inflammation by the means of drugs or supplements (whenever I hear TNF-α, I personally think of curcumin) is not necessarily beneficial.
• The negative side effects will hardly be felt right away. They will rather sneaking up on you after initial health improvements that, when your baseline inflammation went back into the "green zone".

In other words, the lower your baseline inflammation the lower your need for anti-inflammatory agents. This does not mean that you must not keep an eye on an adequate nutritional antioxidant intake, but it should remind you of something people tend to block out, when they go on their supplement shopping sprees:

It's often the pro-inflammatory effect that turns "foods" into "superfoods"!

Take everyone's favorite "health food" as an example: Broccoli and other Brassica vegetables perform their cancer killing magic by the means of sulforaphane, a metabolite of dietary glucosinolates that has been shown to depend on the generation of reactive oxygen species for cancer cell elimination(Singh. 2005).

References:

• Schmeisser S, Schmeisser K, Weimer S, Groth M, Priebe S, Fazius E, Kuhlow D, Pick D, Einax JW, Guthke R, Platzer M, Zarse K, Ristow M. Mitochondrial hormesis links low-dose arsenite exposure to lifespan extension. Aging Cell. 2013 Jun;12(3):508-17.
• Singh SV, Srivastava SK, Choi S, Lew KL, Antosiewicz J, Xiao D, Zeng Y, Watkins SC, Johnson CS, Trump DL, Lee YJ, Xiao H, Herman-Antosiewicz A. Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. J Biol Chem. 2005 May 20;280(20):19911-24.

Pomegranate for Prostate, Rheuma, Breast Cancer, Aromatase, Obesity, Diabetes, Inflammation, HIV, Influenza, Herpes, Crohn's, Hepatitis, Infertility ... You Name It!

Image 1: This drawing from a German 1885 compendium on the flora in Germany, Austria and Switzerland shows that other than Acai & Co, pomegranate is no exotic (expensive and useless) discovery of some fly-by-night supplement vendor.

People are always all the rave, when some clever scientist (or should I say business man?) dug up another of those exotic fruit from a godforsaken valley somewhere in the African or South-American primeval forests. With the hype around ACAI & Co they often forget that there have been real Superfoods just around the corner, right in their local grocery store for years. Pomegranate, as it becomes increasingly evident from recent research, is one of these Superfoods - one that has even been mentioned in the Book of Exodus and has been part of the Ayurevedic tradition for centuries, now. While I have been following the research for some months now, the one mind-boggling study result has always been missing so that this is in fact the first blogpost in quite some time on the "seedy apple" ("pommum", lat. "apple" + "granatus", lat. "grain, seed").

To be precise, this is a post that was triggered by a Facebook message from Lothar, who informed me about the publication of the preliminary results of a phase II trial on the effects of pomegranate extract in prostate cancer prevention (Carducci. 2011).

In all of the 104 patients, whose PSA levels were on the rise after local therapy, the PSA doubling time, which, contrary to absolute PSA values, appears to be a more or less reliable indicator of cancer progression (Semenuik. 2006; Lee. 2005), lengthened by an average of +55% and that regardless of the dosage (1g vs. 3g) the patients received.

This result is unquestionably pretty impressive, it is, however, only part of the picture that has been emerging over the past years. Even if we only include selected studies from the last three months (!), we have to add at least the following health benefits

Image 2: If you consider this pomegranate seed trail long, then you will feel that the list of their health benefits is endless ;-)

• anti-rheumatic, anti-oxidant effect (Balbir-Gurman. 2011),
  reduction in the tender joint count by -62%; -25% reduced free radical-induced lipid peroxidation
• inhibition of glucose-uptake (Kim. 2011),
  -50% Na+-dependent glucose uptake at 424 μg/ml pomegranate extract
• anti-carcinogenic and pro-apoptotic effects (Dikmen. 2011),
  reduces profileration and induces apoptosis (programmed cell death) in breast cancer cells
• cardioprotective selective estrogen receptor modulator (Sreeja. 2011)
  the methanol extract of pericarp of pomegranate is an effective and cardioprotective SERM without some of the negative side effects of tamoxifen, such as increases in uterine weight and proliferation
• anti-obesity effect in diabetics (Gonzalez-Ortis. 2011)
  stops weight and fat gain in 20 obese diabetics
• potent anti-inflammatory (Faria. 2011)
  not limited, but specifically effective in suppressing the NFκ-B pathway
• promotes bone formation in fetus (Monsefi. 2011)
  when given as an extract to pregnant mice (no human data yet)
• antiviral properties (Su. 2011)
  against HIV-1, influenza, herpes, and poxviruses, and human noroviral surrogates
• protective effect against Crohn's disease (Rosillo. 2011)
  attributed to its ellagic acid content
• antioxidant and antiartherogenic effects (Haber. 2011)
  protects from hardening of the arteries due to plaque buildup
• ergogenic and anti-soreness effect (Trombold. 2011)
  pomegranate juice attenuates weakness and reduces soreness of the elbow flexor
• nephro- and hepaprotective effect (Cayir. 2011)
  pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity 
• protective against diet-induced obesity and diabetes (Vroegrijk. 2011)
  dietary pomegrenate seed oil ameliorates high-fat diet induced obesity and insulin resistance in mice, independent of changes in food intake or energy expenditure
• pro-fertility effect / protection against lead poisoning (Leiva. 2011)
  due to its antioxidant activity an ethanolic extract of pomegranate reversed the damage produced by lead acetate on spermatogenesis 
• oral antiplaque effect (Bhadhabe. 2011)
  pomegranate mouthrinse could be long-term antiplaque rinse with prophylactic benefits

to a still preliminary and yet already epic list of health-benefits of an ancient superfruit that is obviously not exotic and exciting enough to compete with the mostly useless, fancy-named herb and fruit extracts people are willing to spend millions of dollars on, year by year... ah, I forgot to mention: the ripe fruit also tastes damn good!