Fat, Sex, and Inflammation: Durga Singer, MA, MD
The world is getting fatter.
Obesity is observed at increasingly alarming rates across the globe. As we have been warned, this will continue to have lasting impact on public health as the rates of cardiovascular disease, diabetes, and other conditions are expected to climb.
Obesity, along with the diseases associated with it, has been closely tied to inflammation and changes in the immune system. Perhaps this is unsurprising, as we have previously discussed the connection between the immune system and other components within the body, like the nervous system and the retina. However, the relationship between the immune system and obesity may fundamentally – and possibly permanently – influence our susceptibility to certain diseases.
Durga Singer, MA, MD
Durga Singer and her lab at the University of Michigan work to decipher the connections between the immune system, obesity, and disease. Durga is a clinician-scientist, and as a pediatric endocrinologist, she sees children in the clinic struggling with obesity and diseases like diabetes. Her interactions with these patients drove her to understand the long-term impact of obesity. In her lab, she focuses on how obesity can influence the development and function of immune cells, which in turn contribute to the chronic inflammation seen in obesity and is associated with metabolic disease progression.
To better understand the source and impact of chronic inflammation in obesity, it helps to understand how it’s different from other forms of inflammation that we may be more familiar with. Inflammation, in general, is a response by the immune system to a stressor that throws off the normal balance of the body’s functions. A bee sting, an infection, stubbing your toe: these are all familiar, real-world examples of stressors that can cause inflammation. Also shared among them is their acute nature. The short-term stressor leads to a sharp inflammatory response by the immune system, but then this is quickly dissipated. This is like washing your hands after getting dirt on them. The dirt is the acute stressor that is a deviation from your normal clean hands. In response, you wash your hands in the sink, turning the water off when you’re done. Short-term problem, short-term response.
In contrast, chronic inflammation is an immune response that’s constantly active at low levels in response to a persistent stressor. Imagine a worn-down washer in your faucet (long-term, low-level stressor) that leads to a constant dripping of water (long-term, low-level response).
In metabolic diseases and obesity, fat tissue – scientifically known as adipose tissue – has been shown to be closely tied to the chronic inflammation of obesity. Obese adipose tissue, experiencing the stress of excess lipids, cell death, and other stimuli, releases compounds called chemokines, which recruit a constant stream of new immune cells to the tissue to create an inflammatory microenvironment. These immune cells, in turn, produce more inflammatory signaling molecules (cytokines) in the adipose tissue leading to tissue impairment that renders the fat cells less sensitive to insulin. Dysfunctional adipose tissue is associated with obesity-associated diseases, including metabolic disease, and the associated enhanced inflammation has been linked to atherosclerosis, cancer, and fatty liver disease.
In addition to dysfunctional adipose tissue, obesity contributes to changes in the immune system overall. Dr. Singer and her lab study the impact of obesity on immune cell function and development. Immune cells originate from hematopoietic stem cells, which undergo a process called hematopoiesis in the bone marrow to give rise to the different cellular subsets of the immune system. Obesity alters the bone marrow environment and modulates hematopoiesis to tilt the process to favor the generation of a certain subset of immune cells. In obesity, this process leads to the production of more cells in myeloid branch of the hematopoietic family tree. Specifically, cells called monocytes, macrophages, and neutrophils are present in higher numbers in obese patients. These cells in certain obese individuals are more pro-inflammatory and contribute to the chronic inflammation and insulin resistance seen in adipose tissue. But this isn’t just seen in fat tissue. Active, pro-inflammatory macrophages have been found in a variety of organs, including the brain, muscle tissue, and liver. Interestingly, markers of inflammation are still seen even after weight loss occurs, suggesting that obesity’s impact on the immune system is not quick to change. The full implications of these observations are still being elucidated, but the impact of obesity on the immune system appears to have long-lasting, body-wide effects.
Through her studies, Durga has found that obesity affects males and females differently. Men and women accumulate fat in different parts of the body, with women generally having a higher percentage of body fat than men, but men having a relatively higher rate of metabolic disease. Dr. Singer has found that sex differences help drive obesity-induced changes of the immune system. Obesity in males leads to the generation of more pro-inflammatory immune cells, especially in the fat tissue around organs (visceral fat), leading to the decreased sensitivity to insulin mentioned above. Obese males also exhibit higher levels of inflammatory signaling molecules (cytokines and chemokines) compared to females, which may contribute to the chronic levels of inflammation.
These differences are due, at least in part, to sex hormones. Researchers have found that estrogens help mitigate the inflammation seen with obesity while protecting against insulin resistance. Conversely, higher levels of inflammatory markers have been associated with decreased estrogen production seen in menopausal women. The role of androgens, however, on obesity-induced inflammation is less clear, though androgens, including testosterone, have been connected to the activation of the immune system in other contexts. The work on the relationship between androgens and obesity-induced inflammation has yielded complicated and somewhat contradictory data. Durga and her fellow researchers will continue to build on these studies as they seek to understand how sex hormones impact the changes in the immune system observed in obesity.
In addition to differences between the sexes, obesity has distinctive effects depending on age. Obesity is increasing across all age groups and understanding the health implications is important. The impact of obesity-induced inflammation may start early in life. Newborns and infants are in a critical period for the development of their immune system. In preclinical rodent studies, postnatal overfeeding induces inflammation in the hypothalamus in the brain, and this inflammatory signaling continued into adulthood, suggesting a long-term reprogramming of the immune system. In humans, this relationship hasn’t been as thoroughly studied. However, rapid growth in the first months of life is a risk factor for metabolic disease, though the underlying biology of this observation is still being uncovered.
The impact of obesity is evident in childhood and adolescence, too. Obese children are more likely to become obese adults. These children exhibit markers of chronic inflammation, including some of those observed in obese adults. For adolescents, obesity has been linked with increased risk for diabetes. Additionally, normal weight adults who were obese as children have a higher risk for diabetes even if they were only obese during childhood. This supports the idea that obesity may significantly affect the immune system for a long-lasting health impact.
There’s also some evidence that the effects of obesity can carry forward to the next generation. Animal studies show that the offspring of an obese mother exhibit increased adipose tissue inflammation, even if the offspring are normal weight. Similarly, offspring of obese fathers are associated with elevated hypothalamic inflammation, which is due to epigenetic changes in the parental sperm. These epigenetic changes influenced what genes are turned on and expressed, contributing to the observed inflammation. While the body of work from human studies on the effect of obesity during pregnancy is small, there are some data that indicate children of obese mothers may have altered metabolic inflammation.
These findings highlight the long-term consequences of obesity and its effects on the immune system on the health of individuals. In addition to the heightened association with cardiovascular disease and diabetes, obesity’s impact on the immune system may hinder our ability to fight pathogens. While obesity causes the number of inflammatory immune cells to grow, these cells appear to be functionally deficient or limited when it comes to fighting pathogens, like lung infections. Understanding how obesity confines the body’s ability to fight infection will be vital, especially in the age of the coronavirus.
Obesity and its impacts on our bodies are significant, long-lasting, and complex. Dr. Singer, with her lab and collaborators, is working to better understand the consequences of obesity and how it affects our immune system. With more knowledge, it may be possible in the future to mitigate some of the consequences of obesity to improve public health and the lives of individual patients.
Special thanks to:
Kanakadurga (Durga) Singer, MA, MD, assistant professor, University of Michigan (ksinger@med.umich.edu)
Qiagen and Todd Festerling for sponsoring the blog
References and further reading:
Singer K and Lumeng CN. The initiation of metabolic inflammation in childhood obesity. J Clin Invest. 2017.
Singer K, et al. Differences in hematopoietic stem cells contribute to sexually dimorphic inflammatory responses to high fat diet-induced obesity. J Biol Chem. 2015.
Varghese M, et al. 2017. The role of sex and sex hormones in regulating obesity-induced inflammation. In: Mauvais-Jarvis F. (eds) Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes, and Obesity. Advances in Experimental Medicine and Biology, vol. 1043. Springer, Cham.