Weight and Inflammation Part 2
This is the Weight and Healthcare newsletter! If you like what you are reading, please consider subscribing and/or sharing!
In Part 1, Dr. Zed Zha, Fellow of the American Academy of Family Physicians) discussed a patient experience that illuminated the need to look beyond simple assumptions about weight and inflammation. In part 2 she will begin a deep dive into the research around weight, weight loss, and inflammation.
Content note: These pieces are extensively referenced, please be aware that the references cited contain weight stigma.
The weight loss industry wants us to believe that “science shows” weight loss leads to less inflammation. Therefore, when you purchase “weight management” programs 1 and anti-inflammatory diet plans,2 you aren’t just pursuing thinness, you are becoming “less inflamed.” And every time new data comes out linking ob*sity and inflammation, it's quickly used as further "evidence" to support the claim that losing weight leads to reduced inflammation.
As a data nerd who earned a bachelor’s degree in theoretical mathematics and a physician who stands against weight stigma, I can’t wait to pick the above statement apart.
To rigorously prove the theorem “weight ↓ → inflammation ↓”, the following four necessary conditions must be met:
Condition 1: Clearly define what constitutes "inflammation" and establish a valid, measurable method for quantifying it.
Condition 2: Measure inflammation both before and after weight loss in the same individuals, ensuring the data show a statistically significant reduction in inflammation.
Condition 3: Demonstrate that weight loss (weight ↓) is not associated with a “paradoxical” increase in inflammation (inflammation ↑), i.e., weight ↓ --/--> inflammation ↑.
Condition 4: If the first three conditions cannot be satisfied, a desperate alternative —proof by contradiction—can be employed: Show that the opposite is not true, specifically, that an increase in inflammation (inflammation ↑) does not correlate with an increase in weight (weight ↑), i.e., inflammation ↑ --/--> weight ↑.
Simple, right? Well, let’s dissect the data in each step and see if this “Q.E.D” upholds.
Defining inflammation and measuring it effectively.
“Inflammation” as a concept of health is thrown around in the “weight loss reduces inflammation” narrative to mean systemic inflammation. In other words, they aren’t talking about eye inflammation like a pink eye, or a big toe inflammation such as a gout attack. The claim here is much broader than a single organ. It’s the entire body, across multiple organ systems. In other words, the weight loss industry wants us to believe that if we lost weight, we would experience a widespread reduction in “chronic, low-grade inflammation” throughout the body, potentially improving overall “health” and reducing the risk of pain, fatigue, indigestion, etc.
How exactly do we quantify THAT?
If there were one number that diagnoses systemic inflammation in a person, it would be easy. But there are over 20 biomarkers in the blood that can be used to indicate the activation of the inflammatory pathways. This single universal marker of inflammation simply doesn’t exist.3
In medical practice, the blood level of C-reactive protein, CRP, a protein released by the liver in response to biochemical stress, is often measured through a lab test to assess inflammation in a certain situation. For instance, I might order a CRP level to see how well a patient suffering from rheumatoid arthritis is responding to treatment. But I would only do that if there were nothing else in the clinical setting that would give us a false positive. This is because CRP is highly non-specific. Besides inflammatory conditions, CRP can be elevated in cases of infection, cancer, psychological stress, and heart attacks. In fact, high sensitivity CRP (hsCRP) is primarily used to predict the risk of cardiovascular disease.4 Since multiple studies have found higher CRP or hsCRP levels in higher weight people, many propose that ob*sity must be an “inflammatory condition.”5
There is a major logical flaw with this conclusion.
In these studies, the participants were controlled for their health status.6 This literally meant all measures of their “health” (age, race, smoking status, inflammatory diseases, even cardiovascular diseases, as defined in the studies) were adjusted to be equal. The only differences were their BMI and CRP levels. In other words, besides these two numbers, the groups were identical health-wise. How does one higher arbitrary number plus another higher arbitrary number equal a health “condition?” It’s like saying studies find people with bigger feet are more likely to visit more shoe stores, therefore, a person with bigger feet has a chronic shopping problem (but really, it’s the fact that many shoe stores don’t carry their sizes and the solution should be to make it easier to buy shoes for feet of all sizes).
Additionally, CRP is classified as an acute phase reactant because its levels increase quickly during infections or injuries which have a fast onset. When young marathon runners’ CRP levels were measured one day after the run, their numbers rose from near 0 to as high as almost 30mg/L and stayed high for days.7 Do all these young, able-bodied people who could get up and run for 4 hours straight have inflammation? Probably not. This leads us to another fun fact: despite all the things we used to infer chronic inflammation, we currently do not have a precise biomarker that can differentiate between acute and chronic inflammation.8
Finally, if CRP is an old story (which it is), let’s look at the “new kid on the block.” In recent years, another biomarker has become popular in the studies on ob*sity and inflammation – the number of macrophages in adipose tissue (AT). This is because macrophages, a type of white blood cells that activate the immune system and clean up dead cells, are the most abundant immune cells in AT.9 Current data suggests that macrophage population in AT is higher in people who have a higher BMI.10 It’s important to know that AT isn’t just deposits of fat. AT is an immunologically active organ, which can act like a reservoir for the immune system in fighting infections.11,12 So, is this increased number of macrophages a sign of inflammation or enhanced immune response?
For the sake of proving a theorem, let’s say it’s true that macrophages are indeed the best measurement of inflammation, i.e., more macrophages = more inflammation. In all these studies, the increased population has been shown in AT, which is a single organ. It doesn’t represent full-body, systemic inflammation as the general public understands it. Saying “ob*sity increases inflammation” remains a gross overgeneralization.
In conclusion, we don’t have a clear definition of systemic inflammation, nor do we have an effective way to measure it. Condition 1: not met.
Proving weight loss leads to less inflammation
In a 2010 mice study, male mice were fed a high-fat diet to reach a high weight before being put on a restrictive diet to induce “gradual” weight loss over 60 days. During the weight loss period, the blood concentration of some inflammatory molecules decreased while others increased. And when the percentage of macrophages was measured in the AT, it increased for seven days before slowly decreasing. But this number never dropped below the control mice who didn’t go through weight-cycling.13 This study has been cited to “prove” that “weight loss gradually extinguishes the inflammatory processes.”14
Well, first of all, this was a study of mice. Male mice, to be exact. Second, AT macrophage population, once again, was equated with AT inflammation. And AT inflammation was then equated with inflammation in general in the study conclusion. As shown in Condition 1, both are sneaky concept swaps at best. Lastly, let’s not overlook the two facts that 1) weight loss initially increased inflammatory markers in these mice which took a long time to recover from, and 2) the weight-cycling mice had higher inflammatory markers than the mice who were never put through it. It sounds to me that we must stop imposing diet culture on rodents and give them food freedom.
Let’s look at some human studies. In 2009, a European clinical research study put 22 fat women on a one-month very low caloric diet (800 kcal/day), followed by a 2-month low caloric diet (600 kcal/day less than estimated energy requirement of the individual), and finally 3-4 months of weight maintenance. The average weight loss was about 10kg over this period of time. When their belly fat was biopsied and analyzed, the gene expression of macrophage markers decreased.15 Similarly, in another study, three months after drastic weight loss from surgery, macrophages were significantly decreased in number in the AT of 17 “m*rbidly” ob*se patients. And the expression of genes that attracted macrophages to accumulate also decreased.16 Exactly like the mice study, the human weight loss trials could only prove a decrease in macrophages in AT, which doesn’t equate to systemic inflammation.
How about inflammatory markers beyond one organ, perhaps in the blood? In 2006, a Greek study recruited 71 fat women and put half on orlistat (a weight loss medicine) plus a restrictive diet and the other half on restrictive diet alone for 6 months. The researchers found a statistically significant reduction of hsCRP in both groups: from 9.3 to 4.1 and 8.5 to 6.6, respectively.17
Does statistical significance translate into clinical significance? As mentioned above, hsCRP is primarily used to predict heart disease risks: a hsCRP level less than 1mg/L predicts a low risk; a level between 1 to 3 predicts a moderate risk; and anything greater than 3 is associated with a highe cardiovascular risk.4 In other words, being on restrictive diets for six months, alone or with a weight loss drug, did not change people’s cardiovascular risk categories. Even if it did, the results still don’t imply a reduction in inflammation because hsCRP (or CRP in general), as established above, is not an effective measure for chronic, systemic inflammation. Indeed, when other markers such as TNF-α and IL-6 were looked at before and after weight loss from surgeries, they did not consistently decrease.18
In conclusion, the evidence for weight loss reducing inflammation is inconclusive at best, if not contradictory. Condition 2: rejected. In Part 3 Dr. Zha will take a look at Conditions 3 and 4.
You may remember back in November that I wrote about a paper that was being teased to the media about a new definition for “ob*sity.” It’s out, and it’s even worse than I thought. A bunch of you have already asked about it so on Saturday we’re going to interrupt this series for a special report on that paper. Between now and then here are three important things to know:
1. It’s not really a scientific article, it’s really just an opinion piece
2. It’s written by people who work in and/or have significant ties to, the weight loss industry
3. It is not a new definition. They are just trying to put a new name on previous failed attempts at defining existing in a higher-weight body as a disease.
For now, you can find Dr. Zha’s substack here and scroll down for reference list
Did you find this post helpful? You can subscribe for free to get future posts delivered direct to your inbox, or choose a paid subscription to support the newsletter (and the work that goes into it!) and get special benefits! Click the Subscribe button below for details:
Liked the piece? Share the piece!
More research and resources:
https://haeshealthsheets.com/resources/
*Note on language: I use “fat” as a neutral descriptor as used by the fat activist community, I use “ob*se” and “overw*ight” to acknowledge that these are terms that were created to medicalize and pathologize fat bodies, with roots in racism and specifically anti-Blackness. Please read Sabrina Strings’ Fearing the Black Body – the Racial Origins of Fat Phobia and Da’Shaun Harrison’s Belly of the Beast: The Politics of Anti-Fatness as Anti-Blackness for more on this.
References
1. Brzezinski D. How Chronic Inflammation May Contribute to Body Weight. Dr B's Blog blog. November 30, https://www.drbnaples.com/link-between-inflammation-and-weight/
2. Awanson k. Inflammation and Weight Loss: A Guide to Shedding 42 Pounds. Live Well Lived blog. November 30, https://www.lifewelllived.fitness/blog/inflammation-and-weight-loss
3. Menzel A, Samouda H, Dohet F, Loap S, Ellulu MS, Bohn T. Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice-Which to Use Regarding Disease Outcomes? Antioxidants (Basel). Mar 9 2021;10(3)doi:10.3390/antiox10030414
4. Bassuk SS, Rifai N, Ridker PM. High-sensitivity C-reactive protein: clinical importance. Curr Probl Cardiol. Aug 2004;29(8):439-93.
5. Das UN. Is obesity an inflammatory condition? Nutrition. 2001/11/01/ 2001;17(11):953-966. doi:https://doi.org/10.1016/S0899-9007(01)00672-4
6. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. Jama. 1999;282(22):2131-2135.
7. Takayama F, Aoyagi A, Takahashi K, Nabekura Y. Relationship between oxygen cost and C-reactive protein response to marathon running in college recreational runners. Open Access J Sports Med. 2018;9:261-268. doi:10.2147/oajsm.s183274
8. Soták M, Clark M, Suur BE, Börgeson E. Inflammation and resolution in obesity. Nature Reviews Endocrinology. 2024:1-17.
9. Lee YS, Olefsky J. Chronic tissue inflammation and metabolic disease. Genes & development. 2021;35(5-6):307-328.
10. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation. 2003;112(12):1796-1808.
11. Trim WV, Lynch L. Immune and non-immune functions of adipose tissue leukocytes. Nature Reviews Immunology. 2022/06/01 2022;22(6):371-386. doi:10.1038/s41577-021-00635-7
12. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Molecular and Cellular Endocrinology. 2010/03/25/ 2010;316(2):129-139. doi:https://doi.org/10.1016/j.mce.2009.08.018
13. Kosteli A, Sugaru E, Haemmerle G, et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. The Journal of clinical investigation. 2010;120(10):3466-3479.
14. Savulescu-Fiedler I, Mihalcea R, Dragosloveanu S, et al. The Interplay between Obesity and Inflammation. Life. 2024;14(7). doi:10.3390/life14070856
15. Capel F, Klimcáková E, Viguerie N, et al. Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. Diabetes. Jul 2009;58(7):1558-67. doi:10.2337/db09-0033
16. Cancello R, Henegar C, Viguerie N, et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. Aug 2005;54(8):2277-86. doi:10.2337/diabetes.54.8.2277
17. Bougoulia M, Triantos A, Koliakos G. Effect of weight loss with or without orlistat treatment on adipocytokines, inflammation, and oxidative markers in obese women. HORMONES-ATHENS-. 2006;5(4):259.
18. Askarpour M, Khani D, Sheikhi A, Ghaedi E, Alizadeh S. Effect of bariatric surgery on serum inflammatory factors of obese patients: a systematic review and meta-analysis. Obesity surgery. 2019;29:2631-2647.
 | A guest post by
|
CRP is used like paint to cover just about everything. One of doctors looked at my previous bloodwork that showed elevated CRP and said, "Yeah, you know what can raise CRP? Really bad seasonal allergies. Pain from autoimmune disorders. A broken bone. A bad job that's giving you severe stress."
As Dr Zha said, CRP is sometimes used to determine risk of heart disease. I remember some years ago when this kept cropping up as "People who have had heart attacks have high CRP levels; therefore, CRP tests prove heart disease." And finally someone with a clue said, "Hey, what was their CRP level before the heart attack?" No answers; the tests were only being done post-event. Perfect example of confirmation bias.
As for weight loss vs CVD risk: I think LOOK AHEAD is a great example here. They took two groups of fat diabetics and put one group on weight loss to see if they'd have less CVD & "early deaths" from heart disease. A 20 year study, it was stopped after just 10 years because both groups were dying at the same rate. (Of course, now the results are being data-mined to pieces to "prove" all sorts of weight loss nonsense, in the same way the Framingham study was.)
I had some trouble understanding the first part of this message, so I recruited a friend who has a graduate degree in theoretical mathematics, and I think there are a couple of typos in your theorem. I'm pointing these out not to discredit your argument but because I think this message is so important and I don't want it to get lost.
Below, I'm assuming "A is associated with B" means "A → B" and "A is correlated with B" means "A & B" because that is my understanding of the words "associated" and "correlated" in this context. If you're using them differently, I'd appreciate the clarification.
First, I believe you intended to use "weight ↓ → inflammation ↓" as the theorem because the theorem you're examining is that weight loss CAUSES a reduction in inflammation, not that weight loss and reduced inflammation are equivalent.
Second, for condition 3, I believe that you meant to write "weight ↓ !→ inflammation ↑".
Third, for condition 4, I believe you meant to write that "inflammation ↑ !& weight ↓". Statements about weight going up are not logically related to any associations with weight going down.