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.

Topical Fat Loss: Capsaicin Cream Blunts Weight Gain in Rodent Model and Increases Leptin, Adiponectin, Lipolysis and Fatty Acid Oxidation in Visceral Fat Depots

Image 1: If you infused your ice-water with an extract of those, that could supercharge your "cold thermogensis" (see "Ephedra vs. Cold Thermogensis" ;-)

Those last 1-2lbs of stubborn fat have been and still are the focal point of countless of discussions among trainees, trainers and  magazines even average Joes and Janes who would not even remotely consider to go to the gym to get rid of those love handles - interestingly, all these groups are similarly susceptible to one message: "Revolutionary breakthrough in topical fat loss: "Whatever-Our-Marketing-Department-Came-Up-With-Burn will obliterate the stubborn body fat that's still covering your abs, obliges, butt, and whatever else you hate about yourself in record time!" Sounds and, as the countless disappointed testimonies on the Internet confirm, is usually too good to be true.

How many scoville (SHU) does it take to burn 1lbs of body fat?

A soon to be published study by researchers from the University of Ulsan in Korea does however show that many of the companies which advertise with the afore "cited" slogans could in fact be on the right track - at least with respect to one of the key ingredients many of those topical fat-burners contain: Capsaicin, a major pungent molecule that is found in hot chilies and other peppers and has already been shown to exert direct effects on isolated adipocytes in vitro (Kang. 2007; Hsu. 2007) and anti-obesity activity in animal models (Yoshioka. 1999; Zhang. 2007). Interestingly enough, epidemiological (Wahlqvist. 2001) and controlled human trials (Bloomer. 2010) suggest that these effect do - despite the often-touted differences in the thermogenic capacity of humans and rodents - in fact manifest in all the usual steps of scientific experimentation in the medical field, i.e. the petri dish, the animal model and the controlled, randomized, placebo-blinded human trial.

From the mouth onto the skin

As far as its topical usage is concerned the main focus of scientific research has yet been on the ameliorative effects of capsaicinoids on painful neuropathies and neuralgia (Harding. 2001; Roberts. 2011) and Lee et al. claim that their study is the first one to investigate the effects of in vivo application of 100mg of a 0.075% hydrophillic capsaicin cream applied to the shaved abdominal skin of pre-fattened mice who were pair-fed (=equal caloric intake for rodents in both groups to exclude reduced appetite as a cause for the observed effect) for 7-weeks.

Figure 1: Body composition (left) and adipocyte size (right) after 7-weeks on HFD with our without topical application of 100mg 0.075% capsaicin cream to the abdomen of obese mice (based on Lee. 2012)

As the data in figure 1 clearly shows, the topical application of capsaicin elicited similar beneficial effects on the blood lipids (not shown) as its oral ingestion in a previous HFD rodent trial (Kang. 2010). What is however particularly striking is that it did at the same time totally blunt further increases in body weight and reduced body fat storage in both the mesenteric, as well as the epididymal, visceral fat depots. The latter went hand in hand with profound changes in the adipocyte morphology of both fat depots which shifted from fewer large, to many small adipocytes - a feature which is usually associated with lower adipocyte inflammation and thus reduced risk of cardiovascular disease & co.

Topical application, systemic effects?

Both results, the improved lipid profile, as well as the reduction in visceral (intra- not super-abdominal) obesity appear to suggest that the effects of the capsaicin cream was by no means as localized as the producers of respective "supplements", would have it.

Figure 2: Adiponectin, leptin, TNF-alpha, lipoprotein lipase, UCP-2 and PPAR expression in mesenteric fat pads of the animals at the end of the 7-week study period (based on Lee. 2012)

The localized decreases in TNF-alpha, a central regulator or inflammation and the profound increases in adipokine expression (adiponectin + leptin), lipoprotein lipase, as well as UCP-2 and all three varieties of the peroxisome proliferator receptors (PPARs), Lee et al. observed in the mesenteric fat pads of the animals do yet confound this theory - capsaicin is, at least partially, a topical fat burner in the literal sense.

Caution! Stimulant-laden fire hazard!

Aside from the fact that its certainly non-negligible effects on visceral fat should not be of great interested for any avid trainee who is following a wholesome whole-foods diet, as those last slabs of body fat that are covering your abs belong to your subcutaneous and not visceral fat depots, there are two more things you should be aware of before you (most likely) waste your money on one of those products.

1. The capsaicin itself will make the body part you rub the product on look like a tomato on fire and burn worse than stinging nettle and that usually for hours!
2. The systemic effects of the stimulants most of these products contain can become an issue especially for leaner folks, as the dosages are usually adjusted for customers with a thick "insulation" that has to be penetrated, first. 

If you still feel that you have to give one or another of those preparations a shot, start with a moderate dose first and wait for a couple of hours to see what it does (don't expect it to do anything to your body fat in that time - if your waistline goes down within the first days of application that's simply water loss!).

My personal recommendation would still be to keep away from any of these products. Regardless of your personal tolerance to stimulants or the specific composition of the different formulas that are currently on the market - 99% of the feedback I have heard and read about states that these products are much better money- than fat-burners  ;-)

References:

1. Bloomer RJ, Canale RE, Shastri S, Suvarnapathki S. Effect of oral intake of capsaicinoid beadlets on catecholamine secretion and blood markers of lipolysis in healthy adults: a randomized, placebo controlled, double-blind, cross-over study. Lipids Health Dis. 2010 Jul 15;9:72.
2. Kang JH, Kim CS, Han IS, Kawada T, Yu R Capsaicin, a spicy component of hot peppers, modulates adipokine gene expression and protein release from obese-mouse adipose tissues and isolated adipocytes, and suppresses the inflammatory responses of adipose tissue macrophages.FEBS Lett. 2007;581:4389-96. 
3. Kang JH, Goto T, Han IS, Kawada T, Kim YM, Yu R. Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity (Silver Spring). 2010 Apr;18(4):780-7.
4. Lee GR, Shin MK, Yoon DJ, Kim AR, Park NW, Yu R, Han IS. Topical application of capsaicin reduces visceral adipose fat by affecting adipokine levels in high-fat diet (HFD)-induced obese mice. Obesity (Silver Spring). 2012 Jun 18. doi: 10.1038/oby.2012.166. [Epub ahead of print]
5. Hsu CL, Yen GC Effects of capsaicin on induction of apoptosis and inhibition of adipogenesis in 3T3-L1 cells.J Agric Food Chem. 2007;55:1730-6. 
6. Wahlqvist ML, Wattanapenpaiboon N Hot foods--unexpected help with energy balance? Lancet. 2001;358:348-9.
7. Yoshioka M, St-Pierre S, Drapeau V, Dionne I, Doucet E, Suzuki M, Tremblay A Effects of red pepper on appetite and energy intake.Br J Nutr. 1999;82:115-23. 
8. Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, Schrader M, Thilo F, Zhu ZM, Tepel M Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity.Circ Res. 2007;100:1063-70.