Obesity: The Doorway to Disease

Obesity: The Doorway to Disease

I want to tighten up the discussion between diet, the gut microbiome, metabolic endotoxemia, and disease just a little, and pull from the previously mentioned list of diseases to do so:

• Insulin resistance
• Obesity
• Diabetes
• Cardiovascular disease
• Autoimmune diseases
• Psychiatric diseases
• Neurodegenerative diseases
• Cancer
• Mortality??

This connection is not some theory to debate. Still, it is a proven metabolic pathway that generates systemic disruption that can lead to many things we call disease—most specifically cancer. Remember, dis-aise is the lack of wellness. Disease is simply an ICD10 code. One imparts the possibility to return to health and wellness. The other is merely a code with no connection to healing or wellness at all.

Diet, gut microbiome, metabolic endotoxemia, and obesity connection.

Obesity is the doorway to disease. Fat tissue, also known as adipose tissue, as inert storage for excess calories and energy storage, is an outdated view on obesity. Worse, it is unscientific. More than not inert, fat tissue is just the opposite, containing significant biologic activity. Adipose tissue produces hormones, regulates immune function, affects metabolism, and stimulates inflammation, to name a few.

Obesity is the physical manifestation of underlying metabolic dysfunction. It is the warning sign that there is something wrong under the hood. Metabolic endotoxemia is at the heart of this metabolic dysfunction. The very phrase metabolic endotoxemia connects the endotoxin to the metabolism effect. I want to look at metabolic endotoxemia’s connection to obesity to highlight some of this resultant metabolic dysfunction.

Two new words, adiposopathy and diabesity, highlight the link between obesity and disease. Adiposopathy points to the broad connection between adipose tissue, “adipos-“ and disease or pathology “-opathy” ^[1]. Diabesity is more specific yet inverse in its connection between obesity, “-esity”, and diabetes, “-diabe” ^[2]. These relatively new words in the English language are an attempt by the scientific community to highlight the link between obesity and lack of wellness—dis-aise. Remember, dis-aise means lack of wellness. We also know this today as disease. These two words, more general concepts, direct the connection between disease back to diet and the gut microbiome through obesity. Beyond the pathway to diabetes, autoimmune disease, and cardiovascular disease, adiposopathy and diabesity link the gut microbiome and obesity to cancer ^[3]. Diet is at the heart of the gut microbiome that leads to obesity or resolves obesity.

But, why the worry? Is not overweight and obesity the new and improved healthy? That is what the tabloid medical journal, Cosmopolitan, published January 1, 2021. From a health and medicine perspective, not image, that is the opposite of the truth. It is hard to describe it as anything other than medical propaganda.

The concept that calories in/calories out are the cause of obesity is outdated and antiquated. Similarly, the idea that the mix of macronutrients, i.e., fats, carbohydrates, or protein, is the cause of obesity is also an outdated and antiquated thought. These thoughts, better-called paradigms that have dominated nutrition for decades, are oversimplified to the point of misrepresentation and unfactual—a faux science. The concept of the food pyramid should be retired to antiquity, just as the Egyptian pyramids have.  It is not that there was a deliberate, intentional misrepresentation of nutrition; but, new knowledge through additional research has come to light that better develops an understanding of the process. Discovery and new knowledge are a part of science and should be a part of medicine. But, if you couple the latest knowledge and discovery with the chronic lack of essential physician reading, the setup is in place for physicians and medicine to practice in a world of faux science. And that is in addition to any bias, unethical, and corrupt contribution to the process.

It turns out that the gut microbiome is the primary contributor to obesity. It is easy to say that diet, calories, and macronutrients are the cause of obesity. That has been the party line for decades now. That statement would be incomplete, and as a result, inaccurate. In fact, the alterations of the gut microbiome resulting from diet, calories, and macronutrients drive the metabolic shift and inflammation that leads to obesity. Of course, method of birth, breastfeeding, antibiotic use, even systemic inflammation can play a significant contributing role, but these topics are beyond the scope of this blog post. The 2019 article, Diet, Gut Microbiota, and Obesity: Links with Host Genetics and Epigenetics and Potential Applications ^[4], lays out three mechanisms of how the gut microbiome causes obesity:

• Epigenetic and genomic modifications
• Excess small chain fatty acid-induced fat deposition
• Metabolic endotoxemia

To be fair, even saying that metabolic endotoxemia is the only way the gut microbiome affects metabolism, inflammation, and obesity is also incomplete science. I believe that the preponderance of the research currently available points to diet as the primary contributor to the cause and effect that results in the alteration of the gut microbiome that results in systemic inflammation—metabolic endotoxemia. It is hard to list genomic modifications as secondary, but for an itemized list, it falls second. The secondary effects are epigenetic and genomic modifications, leading to inflammation, insulin resistance, fat genesis, leaky gut, metabolic endotoxemia, metabolic transformation, and potentially oncogenic metabolic transformation. Third in the list is the excess fatty acid fat deposition. Remember, in addition, to gut microbiome-induced systemic LPS, a high-calorie, high-fat, low fiber diet alone can induce systemic inflammation, and reducing calories and fat intake reduces systemic inflammation ^[5]. Many of the exact mechanisms listed here in the contribution of obesity are involved in the process of chronic disease of aging listed above, and specifically for patients at An Oasis of Healing—cancer. The reason is that they are all on the same continuum. Thus, the connection between obesity and many chronic diseases associated with aging, i.e., diabetes, cardiovascular disease, and cancer. In simple terms, obesity is the doorway to disease.

A foundational study on metabolic endotoxemia and obesity was published in 2007 by Patrice D. Cani and colleagues entitled Metabolic Endotoxemia Initiates Obesity and Insulin Resistance ^[6]. This mouse study was the first to connect diet directly, particularly a high-fat diet, to gut microbiome alteration, LPS induced systemic inflammation (endotoxemia), insulin resistance, obesity, and diabetes. This study noted a decrease in the bacteria Bacteroides, Eubacterium rectale-Clostridium coccoides group, and Bifidobacterium species. Instead of acute LPS spikes, chronic LPS systemic levels led to insulin resistance in the liver. The final result was an increase in weight—obesity.

More impactful, the study found that insulin resistance-driven obesity resulted from the systemic LPS driven endotoxemia and not the excess calories in the high-fat diet. Because this process of metabolic alteration results from altered gut microbiome induced endotoxemia (LPS), which is 10-50 times lower ^[7] than that found in septicemia levels, it was declared to the world as metabolic endotoxemia.

This mouse study proved that the metabolic dysfunction of insulin resistance that drives obesity results from dietary-induced alterations of the gut microbiome. The result is systemic LPS mediated inflammation signaling through LPS-TLR4 signaling. The importance of the impact of LPS-TLR4 interaction cannot be understated. This interaction triggers systemic inflammation from NF-κB transcription.

The cascade effect is even more significant. First, the LPS mediated systemic inflammation increases the number of fat cells—also called adipocytes. It also increases the size of the individual fat cells—adipose hypertrophy. We know these effects all too well. An increase in healthy cells would be a good thing, but hard to see the good in addition to fat cells unless you plan to store excess fat for a long, long winter. Second, the dietary-induced gut microbiome alterations increase glucose absorption from the gut. Third, the result is an increase in systemic blood glucose and insulin level because of the preliminary liver insulin resistance. Fourth, the inflammatory signaling cascade triggers an influx of immune system macrophages into the increased number of fat cells. The result is the production of crown-like cells, which further increases inflammation and insulin resistance to kick the process of metabolic dysfunction further down the road ^[8]. And finally, adipose stimulated crown fat cells to produce inflammatory signaling that alters the gut microbiome—another detrimental loop that feeds on itself.

In conclusion, gut-derived inflammation is passed off and triggers overall systemic inflammation. Though this study did not precisely explain the gut microbiome bacteria and balance that triggers the increase in LPS, it significantly moved the needle to provide more than a connection or association. It proves a direct cause and effect relationship between diet, gut microbiome alteration, and obesity independent of the excess calories in a high-fat diet.

---

I have written previously that obesity is the doorway to disease. Cancer is no exception. The same connection applies between obesity and many cancer types. Beyond the out of date paradigm of cancer as a primarily a genetic disease, many non-genetic contributors to cancer exist ^[9]: Diet, gut microbiome, metabolic endotoxemia, systemic inflammation, hormone imbalance, obesity, cancer connection.

• Tobacco
• Overweight/obesity
• Infection
• Diet
• Alcohol
• Physical inactivity
• Environment
• Medication
• Sun/radiation
• Reproduction
• Family history

Obesity is listed second in the list as it is second in contributing percentage. The actual ranking per country is going to vary. For example, obesity is a bigger problem than smoking. A few decades ago, the opposite was the case. In some European countries, smoking is a more significant driver than a lower obesity rate. In an analysis of the relative risk relationship in increasing weight and cancer, increasing weight and obesity is associated with an increase in the following cancer types ³⁰:

• Uterine
• Esophagus
• Thyroid
• Colon
• Renal
• Liver
• Malignant melanoma
• Breast (postmenopausal)
• Multiple myeloma
• Rectum
• Gallbladder
• Leukemia
• Pancreas
• Non Hodgkin’s Lymphoma
• Prostate
• Breast (pre-menopausal)
• Lung

The argument about whether lifestyle and environmental impacts or genetic drive the pandemic that is cancer that will rage for many years to come. What is abundantly clear is that systemic inflammation is the result of diet induced gut microbiome alterations which leads to disruption of hormone metabolism, contributes to metabolic dysfunction, causes obesity, and directly and indirectly increases cancer risk.

How is all this possible?

It is the vicious cycle of the altered gut microbiome —> adipose tissue —> cancer —> altered gut microbiome—another feedback loop. The alteration of the gut microbiome (also called dysbiosis) in connection with the systemic leak of LPS, leaky gut, leads to an increase in chronic, low-grade systemic inflammation (metabolic endotoxemia), which drives an increase in fact cell size (hypertrophy). The result is an alteration in the local microenvironment that favors tumor initiation, growth, and metastasis. Couple the local tumor microenvironment changes with hormone alterations, immune infiltration, inflammation, changes in endocannabinoid signaling, hypoxia, angiogenesis, and altered metabolism within this local tumor microenvironment, cancer growth, invasion, migration, and metastasis result ^[10].

Is obesity the new healthy? Not according to the science. Obesity is the outward physical manifestation of diet—> altered gut microbiome —> metabolic endotoxemia —> systemic inflammation —> hormone imbalance —> metabolic dysfunction —> obesity —> cancer. Not to critique the connection, but instead to act to better prevent and heal cancer.

---

References

^[1] Yang X, Zhang X, Yang W, et al. Gut Microbiota in Adipose Tissue Dysfunction Induced Cardiovascular Disease: Role as a Metabolic Organ. Front Endocrinol (Lausanne). 2021;12:749125. Published 2021 Sep 6. doi:10.3389/fendo.2021.749125

^[2] Farag YM, Gaballa MR. Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant. 2011 Jan;26(1):28-35. doi: 10.1093/ndt/gfq576.

^[3] Wu J, Wang K, Wang X, Pang Y, Jiang C. The Role of the Gut Microbiome and its Metabolites in Metabolic Diseases. Protein Cell. 2021;12:360–73. doi:10.1007/s13238-020-00814-7

^[4] Cuevas-Sierra A, Ramos-Lopez O, Riezu-Boj JI, Milagro FI, Martinez JA. Diet, Gut Microbiota, and Obesity: Links with Host Genetics and Epigenetics and Potential Applications. Adv Nutr. 2019;10(suppl_1):S17-S30. doi:10.1093/advances/nmy078

^[5] Duan Y, Zeng L, Zheng C, Song B, Li F, Kong X, Xu K. Inflammatory Links Between High Fat Diets and Diseases. Front Immunol. 2018 Nov 13;9:2649. doi: 10.3389/fimmu.2018.02649.

^[6] Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007 Jul;56(7):1761-72. doi: 10.2337/db06-1491.

^[7] Mydel P, Takahashi Y, Yumoto H, Sztukowska M, Kubica M, Gibson FC 3rd, Kurtz DM Jr, Travis J, Collins LV, Nguyen KA, Genco CA, Potempa J: Roles of the host oxidative immune response and bacterial antioxidant rubrerythrin during Porphyromonas gingivalis infection. PLoS Pathog2. 2006:e76.

^[8] Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm. Res. 2019;68:915–932. https://doi.org/10.1007/s00011-019-01273-5

^[9] Wolin KY, Carson K, Colditz GA. Obesity and cancer. Oncologist. 2010;15(6):556-565. doi:10.1634/theoncologist.2009-0285

^[10] Jordan BF, Gourgue F, Cani PD. Adipose Tissue Metabolism and Cancer Progression: Novel Insights from Gut Microbiota?. Curr Pathobiol Rep.2017;5:315–322. https://doi.org/10.1007/s40139-017-0154-6