Key protein EPAC1 found to regulate brown fat growth, offering obesity treatment potential

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In a recent study published in Nature Cell Biology, researchers report that adaptive brown adipose tissue growth is regulated by the exchange protein directly activated by cyclic adenosine monophosphate 1 (EPAC1), a protein that binds to 3′,5′-cAMP.

Study: EPAC1 enhances brown fat growth and beige adipogenesis. Image Credit: Maryna Marchenko / Shutterstock.comStudy: EPAC1 enhances brown fat growth and beige adipogenesis. Image Credit: Maryna Marchenko / Shutterstock.com

Background

Brown adipose tissue plays an essential role in cardiometabolic health, thermogenesis, and energy expenditure. Energy dissipation in brown adipose tissue occurs through non-shivering thermogenesis involving the uncoupling protein 1 (UCP1).

Higher brown adipose tissue mass is associated with a reduced cardiovascular disease risk in adults and leanness. Beige cells are also thermogenic adipocyte cells that can be induced either pharmacologically or due to cold to undergo browning.

Both beige and brown adipocytes are regulated by cAMP. Protein kinase A has been found to play a significant role in the mediation of lipolysis activation by cAMP and energy expenditure through UCP1.

However, cAMP signaling for lipolysis can also occur through EPACs, which are also involved in leptin regulation, insulin secretion in β-cells in the pancreas, and the phosphorylation of protein kinase B in skeletal muscle. EPAC proteins and protein kinase A also have comparable affinities for cAMP.

About the study

In the present study, researchers report that EPAC1 signaling could be pharmacologically and genetically manipulated for energy balance and to regulate thermogenic progenitors. Mouse models were used to analyze the expression of Rapgef3 and Rapgef4 genes encoding EPAC1 and EPAC2, respectively, in different types of adipose tissues.

Energy expenditure was measured through oxygen consumption assessments conducted every 18 hours each day. Mice were housed at colder temperatures for experiments involving long-term exposure to cold, while thermoneutrality experiments were conducted at 30 °C.

Transponders to measure body temperature were inserted into the peritoneum of anesthetized mice. Body temperatures were recorded for mice that were housed in humidity and temperature-controlled environments.

Preadipocytes were isolated from brown adipose tissue obtained from mice that were intraperitoneally injected with 8-pCPT-2′-O-Me-cAMP to selectively and preferentially activate EPAC1, as well as elucidate the role of EPAC1 in the differentiation of brown adipocytes.

Oxygen consumption and body composition of mice were analyzed at regular intervals. Glucose tolerance was measured after intraperitoneally injecting fasting mice with glucose solution. Additionally, mesenchymal stem cells derived from brown adipose tissue were isolated from newborn wild-type mice.

Lentivirus was used to immortalize preadipocytes, which were then cultured in various media to understand brown adipose tissue differentiation. Non-immortalized brown adipocytes were used to understand proliferation using the 5-ethynyl-2′-deoxyuridine (EdU) assay.

High-sensitivity analysis of phosphoproteomics was conducted to understand how cAMP-dependent signaling differed in brown preadipocytes based on the involvement of protein kinase A and EPAC1. Since mitosis and cellular anabolism are essential processes of cell proliferation, the researchers also examined mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 1 (CDK1) signaling.

Primary white adipocytes were isolated from mice between eight and 12 weeks of age. These cells were subsequently cultured and treated with noradrenaline to induce browning or beiging and form beige adipocytes.

Study findings

EPAC1 centrally regulates the adaptive growth of brown adipose tissue through cAMP signaling. The in vivo experiments demonstrated that pharmacologically and selectively activating EPAC1 increased the growth of brown adipose tissue and browning of white adipose tissue, thereby resulting in lower diet-induced obesity and increased expenditure of energy.

The proliferation of thermogenic adipocytes is controlled by a regulator network that is coordinated by EPAC1; however, a similar process does not occur for white adipocytes. Loss-of-function of EPAC1 in preadipocytes also inhibited brown adipose tissue growth and exacerbated diet-induced obesity in mice.

Adrenergic stimulation only induces thermogenic adipogenesis of brown adipocyte tissue and does not induce the proliferation of white adipocytes. This indicates a potential treatment avenue for obesity, as white adipocytes are characteristic of obesity.

Notably, variants of the gene encoding EPAC1 that positively correlated with body mass index inhibited brown adipocyte proliferation that was induced by noradrenaline.

Conclusions

EPAC1 appears to play a significant role in regulating the differentiation and proliferation of brown and beige adipocytes. Thus, this protein could be a potential target for pharmacological activation to promote brown and beige adipose tissue growth, improve cardiometabolic health, and increase energy expenditure. Furthermore, the growth of brown adipose tissue, the subsequent increase in energy expenditure, and the secretion of protective endocrine factors can be used to address metabolic diseases such as obesity and diabetes.

Journal reference:
  • Reverte-Salisa, L., Siddig, S., Hildebrand, S., et al. (2024). EPAC1 enhances brown fat growth and beige adipogenesis. Nature Cell Biology. doi:10.1038/s41556023013119
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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