obesity Archives | Mikhail Blagosklonny Oncotarget

In a new editorial, researchers from Instituto Nacional de Cancerología discuss the obesity paradox and its potential therapeutic opportunities in the context of lung cancer.

The Obesity Paradox, Metformin and Lung Cancer

The strong correlation between obesity and a myriad of life-limiting diseases and conditions, including type 2 diabetes, is widely recognized and acknowledged in the research community. A less defined correlation is that between obesity, diabetes and lung cancer. Whether this association is directly causal or if there are underlying contributing factors is not yet clear.

“Although obesity and type 2 diabetes mellitus (T2DM) have been associated with lung cancer (LC) development, several confounding factors, such as chronic inflammation, high insulin levels, microbiome, as well as the oncogenic potential of growth and sexual hormones, have introduced uncertainty and avoid the fully recognition of this relationship [1, 2].”

Given the existence of this association, scientists are testing therapeutic regimens that may have the potential to fight all three issues — together. Metformin, a drug commonly prescribed to treat type 2 diabetes, helps lower blood sugar levels by improving insulin sensitivity and reducing glucose production in the liver. The metabolic-modifying properties of metformin aid in treating diabetes and obesity. Metformin has also garnered attention for its potential anti-aging properties and may hold promise for treating age-related diseases, including cancer. Lately, there has been growing interest in testing metformin in combination therapies to combat cancer-promoting conditions induced by obesity.

The “Obesity Paradox”

While the link between morbidity and obesity may seem cut-and-dry, researchers have discovered a surprising trend. The “obesity paradox” suggests that, in certain instances, individuals classified as overweight or mildly obese seem to fare better or have a survival advantage compared to those with normal weight or even underweight counterparts. This paradox has been particularly observed in certain chronic illnesses, such as heart failure, chronic kidney disease, and even in the context of aging. Researchers are still striving to understand the underlying mechanisms driving this phenomenon.

In a new editorial, researchers Pedro Barrios-Bernal, Norma Hernández-Pedro, Luis Lara-Mejía, and Oscar Arrieta from Instituto Nacional de Cancerología in Mexico City, Mexico, discuss the obesity paradox and its potential therapeutic opportunities in the context of lung cancer. Their editorial paper was published in Oncotarget on July 1, 2023, and entitled, “Obesity paradox and lung cancer, metformin-based therapeutic opportunity?” They suggest that metformin may have potential therapeutic effects for both obesity and lung cancer. The researchers explore the mechanisms by which metformin may modify tumor metastatic properties and promote an antitumor immune response. They also discuss the potential implications of the obesity paradox in the context of lung cancer treatment and the potential benefits of metformin use in combination with antineoplastic therapies.

In a 2019 study, the researchers conducted a phase 2 randomized clinical trial investigating the effect of metformin combined with tyrosine kinase inhibitors (TKIs) (compared to TKIs alone) in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. They found that the addition of metformin to standard EGFR-TKI therapy in patients with advanced lung adenocarcinoma significantly improved progression-free survival. In their 2022 s tudy, the researchers performed a secondary analysis of the same study, now measuring the association of body mass index (BMI). This time, they reported that the survival outcome in patients with EGFR-mutated lung adenocarcinoma was greater with patients with a BMI higher than 24. The findings suggest that this treatment combination has a selective effect in obese populations and a lack of benefit in patients with a BMI less than 24, thus contributing to the obesity paradox.

“These findings suggest a strong sensitization by the addition of metformin in obese population, suggesting that biochemical and molecular differences influence the treatment response [8].”

Reflections & Future Research

In conclusion, the relationship between obesity, type 2 diabetes and lung cancer remains a subject of ongoing research. Metformin shows promise as a potential multipurpose treatment option, exhibiting properties beneficial for diabetes, obesity, aging, and cancer. The obesity paradox adds a layer of complexity to the obesity-cancer relationship, with some studies suggesting better survival rates and treatment response in overweight or mildly obese individuals treated with metformin. The researchers add that further investigation is needed to determine whether any of the proposed mechanisms of metformin have clinically meaningful activity in the treatment of obese patients with lung cancer. The ongoing research surrounding metformin and its interactions with obesity and cancer may lead to improved therapeutic strategies for these interconnected health challenges.

“Until then, we propose that pharmacodynamics, pharmacokinetics, metabolic parameters, tumor biology, biochemical and molecular modifications may be related to the ‘obesity paradox’ and must be taken into account to choose the most appropriate treatment.”

Click here to read the full editorial in Oncotarget.

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In this 2019 study, researchers investigated the effects of purified elements of cholera toxin in age-associated weight gain.

In recent years, scientists have made significant advancements to improve our understanding of the gut microbiome. This diverse environment—of somewhere around 39 trillion microorganisms living within the digestive tracts of vertebrates (including humans, and even insects)—includes bacteria, archaea, viruses, and fungi. However, a “healthy” gut microbiota remains difficult to define in humans. The contents of the gut microbiome are not only different between women and men, microbiomes differ between… everyone. Among unrelated humans, no more than 30% of the same bacterial strains are shared in the gut microbiome.

Different microbiomes can present with different biological reactions to outside factors, including infections and medications, and can even display different symptoms reacting to cancer and other diseases. Studies have repeatedly found that the gut microbiome plays important roles in human mood, sleep, metabolism, digestion, the immune and nervous systems, and in chronic inflammatory disorders, such as obesity.

“Indeed, earlier studies have shown that gut microbe-immune interactions contribute to smoldering inflammation, adiposity, and weight gain.”

The Hygiene Hypothesis

Researchers continue to find evidence to support the “hygiene hypothesis.” The hygiene hypothesis postulates that a lack of beneficial early-life microbe exposures can result in a dysregulated immune system later in life. This lack of early-life microbe exposures followed by immune imbalances may be responsible for the increase in obesity and other chronic inflammatory disorders over the past forty years.

“Systemic immune imbalances arising from the gut have been proposed as a probable cause of obesity [8].”

In 2019, researchers from Massachusetts Institute of Technology (MIT) and Aristotle University of Thessaloniki conducted a study to test using purified elements of the otherwise dangerous cholera toxin as a vaccination in mouse models. Their theory was that this safe and well-established cholera-based immune adjuvant would cause an immune system reaction that reduces the inflammation associated with age-related obesity. Their research paper was published by Oncotarget and entitled, “Consuming cholera toxin counteracts age-associated obesity.” (Go Behind the Study to learn why the researchers decided to use the cholera toxin.)

The Study

First, the researchers used both inbred and outbred mouse models to test the effects of the cholera-toxin subunit B (ctB)—a component of the Dukoral® vaccine used in humans for cholera diarrhea prevention. For each mouse model tested in the study, four different groups of eight mice each were examined: a female control group, a vaccinated female group, a male control group, and a vaccinated male group. At four weeks of age, the study mice were given three doses every-other-week of ctB at 10 micrograms. The control mice were given sham doses. The researchers found that in ctB vaccinated mice, the oral vaccination prevented age-associated weight gain compared to the control mice in both models.

Next, the researchers used an obese mouse model to test the effects of ctB dosing in early-life and to test the effects of transfering their gut flora into another mouse. The researchers found that the obese-mouse microbiome was sufficient to trigger obesity and inflammation in other mice when compared to sham-dosed control mice. In the obese mouse model, ctB dosing in early life also inhibited age-associated weight gain. This probiotic inhibited weight gain in mice dosed in early-life, and also in mice dosed in adulthood.

“Although we discovered dramatic benefit after early-life exposures to ctB, mice were also significantly slimmer when dosed with ctB for the first time during adulthood at 12-wks-of-age or 24-wks-of-age.”

Conclusion

The researchers found that purified elements of the cholera toxin stabilized immunity, through the gut microbiome, and inhibited age-associated obesity in multiple mouse models. Further studies are necessary to determine the degree to which an early-life microbe exposure such as this impacts immunity versus first-time adulthood exposures. Humans have been taking pre- and probiotics for quite some time without a strong grasp of exactly how these microbe infusions work. This research contributed to a better understanding of how humans can modulate our own gut microbiome to improve many aspects of our health and well-being.

“This type of microbe-immune re-programming may ultimately target other diseases linked with obesity and inflammation such as diabetes [19], multiple sclerosis [64], and cancer [25].”

Click here to read the full research paper, published by Oncotarget.

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