Research on how maternal health affects the fetal immune system and metabolism

At the Varlamov Lab, we combine nonhuman primate studies and advanced basic science methods to study the relationship between maternal health and fetal health. We study nonhuman primates because they closely mimic human pregnancy, immune system development and metabolic function. This makes our findings highly relevant to medicine. At the same time, we are identifying the molecular and cellular pathways that allow maternal health to influence fetal development.

Maternal health factors we study include obesity, Western diet, and use of HIV treatments (antiretroviral therapy). Our unique approach gives us a complete view at the cellular level of how early exposure to these factors in utero leads to inflammatory, metabolic and immune disorders later in life. We use leading-edge techniques including:

• Multiplexed confocal microscopy
• Flow cytometry
• Single-cell transcriptomics
• In vivo transplantation assays
• Metabolic profiling

We also explore the basic biology of adipose tissue. Using live-cell imaging and other advanced methods, we aim to understand how fat cells store and release energy and interact with the local immune system.

Our findings contribute to new treatments for disorders related to obesity and metabolism. What we learn has direct implications for maternal-fetal health.

On this page you can:

• Learn about our research projects
• Find links to our publications
• Meet our team

Accomplishments

• First to show that maternal Western diet in nonhuman primates leads to long-lasting immune system dysfunction in offspring.
• Developed an image-based toolkit to streamline microscopic anatomy assessment of adipose tissue.
• Pioneered a live-cell imaging approach for studying adipose tissue that preserves insulin sensitivity and allows for detailed analysis of fat metabolism ex vivo.
• Established a model for translating antiretroviral therapy’s effects in nonhuman primates to human maternal-fetal interactions.

Effects of diet and obesity during pregnancy on the fetal immune system

More than 30 percent of reproductive-age women in the United States are obese, and research has shown that obesity can affect the long-term health of their babies. Working with researchers at the University of Kentucky, the University of Oklahoma, and the University of Colorado, we are studying babies born to pregnant nonhuman primates who are obese or eat a Western diet high in fats and sugars.

Other researchers have started to understand these effects, but the reasons for them at a cellular level remain poorly understood. We first explored how obesity and Western diet affect the development of hematopoietic stem cells.

These specialized cells produce all types of blood cells throughout the lifespan. Our findings show that fetal stem cells exposed to a maternal Western diet in utero have impaired function. For example, the myeloid cells they form use less oxygen for energy and rely more on sugar. This leads to inflammation and the effects can last for years, even after the offspring switches to a healthier diet. This makes these offspring more likely to develop inflammatory diseases later in life.

Overall, our research shows how important it is to maintain a healthy weight during pregnancy.

Effect of antiretroviral therapy on fetal immune system development

More than 1 million women living with HIV give birth each year. Combined antiretroviral therapy is an effective way for pregnant and breastfeeding parents to prevent transmission of HIV to their babies. However, many antiretroviral drugs make their way into the placenta and then to the fetus. HIV-exposed but not infected (HEU) children face medical problems. They are more likely to die from infections or have severe respiratory problems.

We study pregnant monkeys infected with SIV (simian immunodeficiency virus). The antiretroviral therapy for SIV closely mirrors the therapy used in humans with HIV. This allows our findings in monkeys to offer insights that could inform how we treat humans.

We are working with Benjamin Burwitz, Ph.D., to test our hypothesis that both SIV and antiretroviral therapy affect fetal immune system development. We aim to show how each exposure impacts the immune system at the cellular level.

Physiology of white adipocytes

Adipocytes (fat cells) are the body’s primary energy reservoir. They store neutral lipids in the form of esterified fatty acids. When energy is needed, adipocytes release fatty acids, which are used by mitochondria in other cells to produce energy. This process, known as mitochondrial beta-oxidation, is well-established in both brown and white adipocytes.

White adipocytes are large cells that contain a single lipid droplet and have a small cytoplasmic volume. But their fragility makes it challenging to study how they store and transport lipids. To overcome this limitation, we developed a method to isolate and culture white adipocytes while preserving their insulin sensitivity. This approach enables live-cell imaging, so we can observe their function in real time.

Our work provides valuable insights into white adipocyte biology and their behavior under different conditions, advancing our understanding of lipid storage and metabolism.

Confocal microscopy of mitochrondrial mobility

Publications

Find more publications by Dr. Oleg Varlamov on PubMed.

Adipose Tissue Analysis Toolkit (ATAT) for automated analysis of adipocyte size and extracellular matrix in white adipose tissue
Obesity, August 2024
Robino JJ, Plekhanov AP, Zhu Q, Jensen MD, Scherer PE, Roberts CT, Varlamov O

Aging human abdominal subcutaneous white adipose tissue at single cell resolution
Aging Cell, November 2024
Whytock KL, Divoux A, Sun Y, Pino, MF, Yu G, Jin CA, Robino JJ, Plekhanov A, Varlamov O, Smith SR, Walsh MJ, Sparks LM

Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates 
JCI Insight, Sept. 24, 2024 
Webb G, Sauter KA, Takahashi D, Kirigiti M, Bader L, Lindsley SR, Blomenkamp H, Zaro C, Shallman M, McGuire C, Hofmeister H, Avila U, Pessoa C, Hwang JM, McCullen A, Humkey M, Reed J, Gao L, Winchester L, Fletcher CV, Varlamov O, Brown TT, Sacha JB, Kievit P, Roberts CT

People

The Varlamov Lab is led by Oleg Varlamov, M.D., Ph.D., a medical biochemist and molecular pharmacologist. Dr. Varlamov’s research uniquely integrates nonhuman primate studies with advanced cellular and molecular techniques.