One of the diseases most extensively investigated in the immunology field today is diabetes, a common disorder associated with obesity - a complex condition that can have a profound effect on the immune system.
While food shortage and malnutrition have been a common scenario throughout human history, the worldwide public health crisis caused by the epidemic of obesity is relatively recent. Obesity, as described by the U.S. National Institute of Environmental Health Sciences and the World Health Organization (WHO), is a condition involving excessive body fat accumulation beyond standards (humans are considered overweight when their body mass index or BMI is in the range of 25-30 kg/m2). The “western diet,” consisting of high fat, cholesterol, sugar and salt intake and mostly involving processed fast food, plays an important role in the development of this condition.
Scientific research has demonstrated that obesity develops due to diverse causes that include environmental and/or genetic factors, yet lifestyle factors such as poor diet, insufficient exercise, social determinants and geographic location are becoming more relevant in our time. Unfortunately, because of its complexity, obesity is likely one of the most difficult public health issues our society must face.
At present, more than a third of Americans (42%) are classified as obese (one of the highest percentages of obese people in the world), and humans continue to accumulate more fat on their bodies today than in any other given time in history. This results in a currently estimated medical cost of nearly $150 billion every year in the U.S. alone, making obesity one of the biggest public economic health burdens of our time. Fortunately, although obesity has become an epidemic at an alarming rate, it is a condition partially preventable by reducing caloric intake and engaging in physical exercise. Caloric restriction (CR) has long been established as a beneficial habit that increases lifespan and decreases mortality and morbidity. The gradual deterioration of the human body associated with aging is somewhat similar to the effects of obesity. Hence obesity is considered to resemble a premature aging condition. In fact, it has been observed that obesity can reduce life expectancy by up to 20 years. This scenario represents a perfect example of the known proverb “we are what we eat” and helps illustrate the importance of a healthy diet and physical exercise.
Autophagy and the Immune System
One of the most ancient and critical processes occurring in almost every living cell is autophagy, and it can be affected by fat accumulation. This is an essential catabolic process through which cellular components are degraded and reused/repurposed. You can think of it as the stomach of the cells, where cellular components can be degraded into elemental units, such as fatty acids (FAs) or sugars, that become useful in the synthesis of new cellular structures and the production of energy to maintain cellular functions. Just like eating a meal that gets digested into its essential components that we call nutrients to give us the energy we need. But autophagy does much more than digest. This process regulates responses to different stresses or functional states within the cell and has specific functions in different cells types of the immune system. It constitutes a very important pathway whose proper regulation can have an immense impact on the generation of an immune response. Obesity, through its impact on autophagy, can have a substantial negative effect on the immune system, significantly hindering its ability to defend the body against pathogens.
How can this happen exactly? Only recently have we begun to understand the specific mechanisms by which FAs influence autophagy, but it has been demonstrated that deregulation of autophagy results in a detrimental effect on cells. Providing a connection between nutrition, autophagy and the immune response, it has been proven that defective regulation of some immune cells is due to an inability of these cells to mobilize lipid stores and efficiently generate the energy necessary to maintain their functions. Additionally, scientific research has shown that FAs can directly interfere with specific steps of autophagy on T cells, leading to a deregulated immune response. If the cell can’t “digest the food,” it can’t function properly.
Interestingly, the complex relationship between fat and immune function seems to be dependent on a threshold level. Above a certain level of FAs, immune cells decrease their function (failing to protect the body against disease), but below this level, immune cells can increase their function beyond what is needed, creating an overwhelming response that causes more harm than good. Therefore, obesity may cause increased basal activation of different immune cells, inducing chronic inflammation and damage to tissues and organs, but also inhibition of T cell responses, contributing to a poor immune response.
An excellent example is the observed higher risk of severe illness and death from COVID-19 in overweight and obese individuals. Researchers have found that SARS-CoV-2 is prompt to infect both fat cells and certain immune cells within body fat, inducing a damaging, overwhelming defensive response in the body. Fat can also serve as a reservoir for pathogens, meaning that an overweight individual could be carrying the virus, which patiently awaits its opportunity to thrive, much like the Trojan Horse.
Industry to the Rescue
These are just a few examples of the many detrimental health effects of excessive body fat. The pharmaceutical industry is well aware of the obesity epidemic and has been eager to contribute to an area that carries with it the potential for explosive commercial growth. Several large pharmaceutical companies made a splash with weight-loss treatments in the 1990s. But even when proven successful, these have not solved the obesity problem due to the diverse causes of its pathology.
One company leading the scientific innovation in this space is ERX Pharmaceuticals which focuses on Leptin, a hormone produced by fat cells and discovered 28 years ago that controls appetite, food intake and energy expenditure by telling the brain whether to eat more or less and how much energy to spend.
The obese population generally has high circulating leptin levels, leading to the hypothesis that obesity is a condition of leptin resistance. Based in Cambridge, Massachusetts, and building on the discoveries of Dr. Umut Ozcan, an associate professor at Boston Children’s Hospital and Harvard Medical School, ERX is developing leptin sensitizers as drug candidates for the treatment of obesity. This could represent a safe, well-tolerated and effective approach to decrease appetite and food intake, without the decrease in energy expenditure typically seen in weight loss medications. Its lead asset, ERX-1000, is currently being evaluated in a double-blind, placebo-controlled Phase I clinical trial led by Dr. Irene Mirkin, and results are expected in Q1, 2022. Additionally, the company is looking to apply this knowledge to other obesity comorbidities such as type 2 diabetes. To date, ERX-2000 has shown anti-diabetic activity and weight-lowering ability in preclinical animal models.
A different approach comes from Swedish pharmaceutical Empros Pharma, which aims to delay normal food digestion and absorption processes toward the end of the small intestine, increasing the natural endogenous satiety response and decreasing food intake. Conventional oral pharmaceuticals targeting this strategy usually reduce or delay the absorption of fatty acids or sugars in the intestine, which can cause diarrhea and reduce tolerability and efficacy. Empros’ approach with its lead candidate, EMP16, intends to increase efficacy by optimizing this breakdown, triggering a satiety response while decreasing undesired side effects. In 2017, EMP16 completed a Phase IIa study of 64 subjects evaluating the effect on appetite/tolerability score after two weeks of treatment with three different dose combinations, as compared to Xenical®. A Phase IIa proof-of-concept golden standard randomized, placebo-controlled, double-blinded clinical trial began in 2020, comparing two different doses versus placebo in achieving weight loss after 26 weeks.
Almost all marketable drugs used to treat obesity today are appetite suppressants, which often lead to a great deal of discomfort due to undesirable side effects. Lobesity, an early-stage company founded in 2015 by researchers M. Michael Wolfe, M.D. and Michael O. Boylan, Ph.D., and based in Cleveland, Ohio, is tackling the underlying causes of obesity to avoid the undesirable side effects of other oral pharmaceuticals. Lobesity focuses on insulin, the most potent hormone known to promote the synthesis and storage of carbohydrates and lipids while inhibiting their breakdown. Greater insulin release means higher glucose absorption from the intestine, which results in increased glucose uptake into fat cells. By targeting incretin hormones that promote insulin release upon overnutrition, Lobesity’s humanized monoclonal antibody against gastric inhibitory polypeptide (anti-GIP mAb), aims to decrease insulin levels which in turn reduces glucose uptake into fat cells. Ultimately, this could yield weight loss and prevention of weight gain. Currently, the anti-GIP mAb is being prepared for human clinical testing and early results in mouse models have already shown great promise, even to the point of reversing obesity.
A revolutionary approach focused on what has been traditionally known as the “powerhouse of the cell” comes from CohBar. Based in Menlo Park, California, CohBar was founded by pioneers in the field of aging and metabolism focused on developing treatments for chronic diseases by harnessing the power of mitochondrial biology. Using a proprietary platform, CohBar is developing analogs of natural peptides encoded in the mitochondrial genome as potential treatments to treat mitochondrial defects or abnormalities commonly observed in multiple diseases. Its lead candidate for the treatment of obesity and non-alcoholic steatohepatitis (NASH), CB4211, is a novel peptide currently under clinical investigation. In August 2021, the company released positive topline data from its Phase Ia/Ib clinical study in 65 healthy subjects, which showed robust and statistically significant improvements in glucose levels with a trend toward lower body weight. The company is growing and pioneering the field of mitochondrial medical research, and went public just four months ago. (NASDAQ: CWBR).
As our scientific knowledge advances, it has become evident that most diseases are complex by nature and not one pill can cure us all. The latest breakthroughs in personalized medicine, tailored to patients’ genetic profiles, and our understanding of the complexity of the immune system, have revolutionized the treatment of multiple cancers, and a similar approach will need to be applied in clinical practice for conditions such as obesity. The diversity of these pharmaceutical companies in their approach is encouraging, and 2022 will likely see new companies entering the R&D landscape focused on specific patient subsets that make them stand out among the competition.
While we can count on the scientific community to help solve this epidemic, we must understand that humans and every other organism on the planet are heavily impacted by the environment, including diet, and that the first step to a healthy life is a healthy diet.
https://www.biospace.com/article/the-epidemic-of-obesity-and-its-impact-on-the-immune-system/
