The Scientific Sessions symposium Single-Cell Perspectives on Metabolic Tissue Function featured a panel of investigators who discussed new and ongoing research using single-cell technologies to explore the roles of adipocytes, macrophages, beta cells, and fibroblast growth factor-1 in metabolic tissue function.
The session, which was originally presented Tuesday, June 29, can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.
Qiong (Annabel) Wang, PhD, Assistant Professor, Department of Molecular and Cellular Endocrinology, City of Hope Diabetes & Metabolism Research Institute, discussed the metabolic and functional heterogeneity of adipocytes, including the association between adipose tissue dysfunction and insulin resistance and metabolic disorders.
“When fat tissue expands through adipogenesis of free adipocytes, these newly generated adipocytes are considered to be metabolically functional, and there’s always a very active angiogenesis during this process,” Dr. Wang explained. “On the opposite, when fat tissue expands through hypertrophy, which is simply an increase of adipocyte size, they become metabolically dysfunctional and there is increased fibrosis, hypoxia, and necrosis. So, the clinical results from these two types of fat expansion could be quite different.”
Dr. Wang is studying how to determine whether adipogenesis has taken place during a certain period of time and the association between age and adipose tissue expansion.
“We found that age-associated adipose tissue expansion in mice mimics human sarcopenic obesity, and it happens in the middle-aged to aged population, and adipose tissue accumulates with age through massive adipogenesis, especially in the visceral site,” she said. “Adipocyte progenitor cells (APCs) from aged mice have a greater adipogenic potential in vivo, and we think that aging globally shifts APCs and generates an age-specific committed preadipocyte (CP-A) population. Most importantly, we found that, besides a higher proliferation rate, the CP-A population also has a much greater adipogenic rate in vitro.”
Christopher K. Glass, MD, PhD, Professor of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, described research using dynamic enhancer landscapes as the basis for understanding myeloid cell diversity, specifically in the context of nonalcoholic steatohepatitis (NASH).
“In addition to their core function in innate immunity, we know that macrophages play a number of tissue-specific roles dependent on the specific organ in which they reside,” Dr. Glass said. “And in addition to these adaptive functions, we also appreciate that macrophages are major contributors to a variety of human diseases and actually drive tissue injury and tissue pathology.”
One of the outstanding questions in the field of macrophage biology relates to how these cells, which are normally adaptive, transform into cells that drive tissue injury, he said.
“Our major approach to addressing this question is to try and understand the transcriptional mechanisms that control the development and function of macrophages, both in the context of normal homeostasis and also in the context of disease. This has focused our attention on promoters, which are the obligatory start sites of messenger RNAs and enhancers,” Dr. Glass said. “Our general conclusions are that dynamic enhancer landscapes can provide insights into transcription factors and upstream signaling pathways that establish tissue and disease-specific macrophage phenotypes.”
Heiko Lickert, PhD, Professor and Chair of Beta Cell Biology, Technical University of Munich School of Medicine, Germany, and Director, Institute of Diabetes and Regeneration Research, discussed the use of single-cell technologies to decipher mechanisms of beta cell failure and regeneration.
“We want to protect or regenerate beta cells, but this is still not possible except for two treatments that are in the clinic, but which are invasive—islet transplantation, often used for critical type 1 diabetes patients, and/or bariatric surgery for morbidly obese people,” Dr. Lickert said. “These two surgical treatments can cause diabetes remission, but we would really like to understand how we can protect or regenerate beta cells by noninvasive measures.”
In his work using single-cell technology, Dr. Lickert analyzed beta cell dedifferentiation in a diabetes model and identified new targets for intervention.
“We defined dedifferentiation markers, but also potential surface markers to target these diabetic beta cells,” he said. “We have shown that with pharmacological intervention, with insulin signaling, you can basically re-differentiate these cells.”
Michael W. Schwartz, MD, the Robert H. Williams Endowed Chair in Medicine and Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, discussed research examining fibroblast growth factor-1 (FGF-1), which acts in the hypothalamus of diabetic animals to promote sustained remission of diabetic hyperglycemia.
“We and others have shown that, especially in rat and mouse models of diabetes, there are interventions that can be used to target the brain that don’t simply lower the blood sugar level the way that insulin would, but actually normalize the defended level of glycemia in diabetes. And in the case of FGF-1, this effect can be sustained over long time intervals,” Dr. Schwartz said. “It’s also emerged recently from our work and others that the mediobasal hypothalamus appears to be the primary brain area capable of eliciting this type of response.”
Dr. Schwartz presented data indicating that diabetes remission induced by FGF-1 depends on intact melanocortin signaling, and also appears to depend on intact perineuronal nets, suggesting a potential link between them.
“It’s the glial responses to FGF-1 that evolve over time, and we hypothesize that these responses silence overactive mediobasal hypothalamic circuits and that this effect, in turn, restores blood glucose levels to normal by increasing melanocortin signaling and increasing perineuronal net,” he said. “Unlike current treatments for type 2 diabetes, brain-directed strategies have the potential to restore the defended level of blood sugar to normal in a sustained manner.”