Introduction
According to the National Heart, Lung, and Blood Institute, about one in every three American adults has a metabolic disorder, which were responsible for 33.1% of deaths in the United States in 2019. This silent yet profound epidemic that has swept the nation has been long in the making as metabolic risk factors, such as high blood pressure, high blood sugar, and excess fat, become increasingly prevalent in today’s society. These disorders are characterized by conditions such as obesity, diabetes, and lipid metabolism dysfunction. Not only do these disorders burden individuals with chronic health challenges, but they also harbor a more covert consequence: their impact on immune function. While often viewed as separate systems, the metabolic and immune systems share an intricate relationship, where disruption in one system can reverberate through the other. Understanding how metabolic disorders affect immune responses is critical to understanding their role in the rising incidence of infections and chronic inflammatory diseases.
What Are Metabolic Disorders?
Metabolism encompasses the chemical processes that sustain life, enabling the body to convert food into energy and support vital functions. Metabolic disorders arise when these processes are disrupted, leading to significant health complications. Obesity and Type 2 diabetes (T2D) are among the most prevalent metabolic disorders and share overlapping risk factors. For instance, chronic low-grade inflammation, a hallmark of obesity, makes individuals more susceptible to immune dysfunction. Similarly, high blood sugar levels associated with T2D can weaken an individual’s immune system by altering the body’s ability to fight infections and respond to injuries. These connections underpin the importance of understanding the relationship between metabolism and immunity, prompting the question: How do metabolic disorders affect the immune system?
The immune system, a complex network of cells and molecules, serves as the body’s primary defense mechanism against pathogens. Immune cells rely heavily on metabolic pathways for their activation, proliferation (rapid growth), and function, which are easily disrupted by metabolic disorders. Insulin resistance, which inhibits the uptake of sugar, also compromises immune cell signaling, and obesity-induced inflammation leads to the overactivation of immune pathways, contributing to tissue damage. Dysregulated metabolism further impairs the energy supply needed for proper immune responses, exacerbating inflammation and disease progression. Such findings highlight the dual role of metabolic disorders in both weakening immune defenses and perpetuating chronic inflammation.
Kupffer Cells
To uncover the link between metabolic disorders and the immune system, the Saltiel Lab at the University of California San Diego School of Medicine focuses on the intersection between obesity and inflammation, and their effects on adipose, or fat, and liver tissues. This includes studying their effects on Kupffer cells, the liver’s resident macrophages, which are immune cells that play a key role in maintaining liver health and regulating immune responses, allowing our bodies to maintain homeostasis and produce glucose for energy. The Saltiel Lab’s research redefines obesity as not merely excessive caloric intake, but as a systemic condition of persistent mild inflammation that significantly impacts immune and metabolic pathways.
Obesity triggers an immune response characterized by the activation white blood cells called monocytes, increased circulating inflammatory markers, and the infiltration of macrophages into adipose tissue. Using a high-fat diet model in mice, the Saltiel Lab has demonstrated how obesity alters the inflammatory properties of adipose tissue macrophages (ATMs) and impairs the ability of fat cells, or adipocytes, to store energy. Specifically, these proinflammatory ATMs release cytokines that reduce the insulin sensitivity of adipocytes, disrupting glucose and lipid metabolism, and contributing to the onset of diabetes. In lean mice, resident macrophages maintain tissue homeostasis while high-fat diets lead to the recruitment of pro-inflammatory M1 macrophages, which dominate the adipose tissue environment and perpetuate persistent mild inflammation. This sustained inflammatory response not only disrupts immune equilibrium, but also has systemic consequences. Similarly, Kupffer cells undergo a shift toward a pro-inflammatory state in obesity, amplifying immune dysfunction. Their hyperactivation fuels liver inflammation and disrupts insulin signaling in the liver, increasing metabolic dysregulation. Pro-inflammatory cytokines released by M1 macrophages trigger immune dysregulation, including the activation of T-cells, further amplifying inflammation. Chronic inflammation also diminishes the ability of regulatory, anti-inflammatory immune cells like M2 macrophages to resolve inflammation, creating a feedback loop of immune overactivation. This dysregulated immune state exacerbates insulin resistance, suppresses energy expenditure, and weakens immune defense against pathogens, making individuals more vulnerable to infections and delayed wound healing. In the liver, this imbalance is amplified as Kupffer cells lose their homeostatic function and contribute to the infiltration of additional liver macrophages, perpetuating the inflammatory environment that drives insulin resistance and metabolic dysfunction.
The Saltiel Lab seeks to pinpoint the early molecular events that initiate inflammation in obesity. By identifying triggers and signal cascades, the lab aims to uncover new strategies for preventing the progression of metabolic disorders, focusing on the cross-talk between immune cells and adipocytes to understand how chronic inflammation in obesity drives systemic metabolic dysfunction. This integrative research provides a foundation for innovative therapeutic strategies aimed at breaking the cycle of metabolic and immune dysfunction.
Building on the exploration of inflammation’s role in metabolic disorders, Dr. Ishtiaq Jeelani’s work in the Olefsky Lab at the UC San Diego School of Medicine investigates the immune mechanisms underlying metabolic inflammation in conditions like nonalcoholic steatohepatitis (NASH), a cluster of metabolic disorders characterized by the accumulation of excess fat deposits in the liver. More specifically, Dr. Jeelani observes the activity of Kupffer cells during proinflammatory responses of recruited macrophages activated in NASH. Kupffer cells are master strategists, constantly interpreting metabolic and immune cues to decide whether to fight or remain at peace. But in chronic disease, their precise judgment falters, leading to unintended destruction.
In NASH, Dr. Jeelani observed that Kupffer cells and M2 macrophages are killed due to hypoxia, or lack of oxygen, and increased metabolic demands, contributing to severe health problems such as fibrosis. While investigating the culprit behind the Kupffer cell killers, researchers at the Olefsky Lab uncovered HIF-2α, a protein responsible for adaptation to low oxygen levels. Using CRISPR, a genetic editing tool that enables targeted gene disruption, Dr. Jeelani specifically knocked out HIF-2α from a cohort of mice without impacting any other genes. Two groups of mice, one with HIF-2α and one without HIF-2α, were then fed a diet consisting of fatty, unhealthy foods dubbed the “Western Diet.” As expected, the livers of mice lacking HIF-2αwere abnormally enlarged and characterized by tumors, while mice with the HIF-2α protein had healthy livers. However, mice with the HIF-2α experienced significant Kupffer cell death, indicating that HIF-2α directly caused Kupffer cell death, which accelerated liver disease in NASH-afflicted mice. Thus, knocking out HIF-2α using CRISPR could potentially enhance the metabolic health of the liver and mitigate liver damage in mice exhibiting NASH in future experiments.
By leveraging cutting-edge tools like CRISPR, Dr. Jeelani’s work in the Olefsky Lab has provided critical insights into the intersection of immune and metabolic systems, particularly in the context of liver diseases like NASH. Their research demonstrates how immune cell dysfunction contributes to metabolic imbalances, paving the way for novel therapeutic strategies and for the exploration of how immune cells, such as macrophages, regulate metabolic processes by influencing inflammation.
The Bigger Picture:
Metabolic disorders like obesity, diabetes, and NASH are not just isolated health issues; they are part of a larger systemic imbalance that intertwines with immune dysfunction, driving chronic inflammation and disease progression. Research at UC San Diego is illuminating this critical relationship, offering hope for therapies that target the root causes of these interconnected epidemics and can reshape the future of metabolic and immune health.