Harnessing Adipose Tissue to Treat Obesity

Alexander Knights, PhD Postdoctoral Fellow and Carolyn M. Walsh, PhD Postdoctoral Fellow, Molecular & Integrative Physiology

When it comes to adipose tissue, the “white” adipocytes (fat cells) get most of the attention. They’re well-known for their role in storing excess energy from food intake in the form of lipids and releasing it when it’s needed by other parts of the body. “Brown” or “beige” adipocytes, on the other hand, actually expend energy themselves by producing heat in a process known as thermogenesis. This remarkable ability has long made them an exciting target for researchers interested in metabolic diseases: figuring out how to activate thermogenic adipocytes so that they burn off more energy is seen as a highly promising treatment for obesity. Despite their potential, scientists to date have had limited success with harnessing these cells for therapeutic purposes.

Things took a turn in 2018, when Jun Wu’s lab in the University of Michigan’s Molecular and Integrative Physiology Department published a paper in Nature Medicine(1) reporting the discovery of a new signaling pathway for this coveted process. Adipose tissue is composed not just of adipocytes, but of various other cell types including immune cells. The Wu lab found that these adipose-resident immune cells can secrete a molecule called acetylcholine, which then goes on to promote energy expenditure by driving thermogenesis in beige adipocytes. However, it was unclear exactly which immune cell was responsible for secreting acetylcholine, and the lab has since focused on unmasking the culprit as well as elucidating the mechanisms that underlie this novel pathway.

Dr. Alexander Knights, a postdoctoral fellow who hails from Australia, was up to the challenge. He used a fluorescent molecule linked to the enzyme responsible for synthesizing acetylcholine, which meant that his cells of interest – those that produced acetylcholine – were much easier to identify, since they all expressed green fluorescent protein (GFP). Dr. Knights found that multiple types of immune cells from the adipose tissue synthesized acetylcholine. Therefore, to narrow his candidates down further, he took mice whose acetylcholine-producing (or “cholinergic”) cells expressed GFP and exposed them to cold temperatures. Cold exposure is well-established as a stimulus that increases thermogenesis, so Dr. Knights knew that the cholinergic cells important for kick-starting the thermogenic program should respond. Sure enough, when he examined GFP-expressing cells from the adipose tissue of cold-exposed mice, he found that only one population had increased: the macrophages, a type of immune cell involved in a wide variety of inflammatory processes. What’s more, knocking out the enzyme response for acetylcholine synthesis in the macrophages, but not other types of immune cells, left the adipose tissue impaired in its ability to effectively activate thermogenesis in response to cold exposure, underscoring the importance of cholinergic macrophages in this pathway.

Dr. Knights and his colleagues also found that cholinergic macrophages depended on a particular type of receptor called the β2-adrenergic receptor for synthesis and secretion of acetylcholine. These findings are especially promising given that previous attempts to harness the potential of thermogenesis for the treatment of obesity relied on another receptor, the β3-adrenergic receptor, which resulted in problematic cardiovascular side effects. The β2 receptor is an alternative target that may provide a more effective and safe strategy to activate thermogenesis and promote energy expenditure via the macrophage-adipocyte cholinergic signaling axis identified by the Wu lab.

Alex doesn’t regret moving from the other side of the world for his postdoctoral work. Although he was originally drawn to work with Dr. Wu because of her expertise in adipose tissue-resident immune cells, he says that he’s also benefited immensely from the scale of University of Michigan’s research enterprise, which has enabled him to collaborate widely with other investigators and expand his professional network. Support from the Michigan Life Sciences Fellowship, a program that provides a generous salary, funding for independent research and a tight-knit community, hasn’t hurt either. These benefits have given Alex the flexibility to pursue his own scientific interests and a level of financial security that lets him relax and focus on his work.

Something else Dr. Knights can teach you that you might not have known? Australia’s population is only 25 million, but in terms of land mass, it’s about the same size as the contiguous United States. “It’s big,” explains Alex. •