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

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 three′,5′-cAMP.

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


Brown adipose tissue plays an important 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 related to a reduced heart problems risk in adults and leanness. Beige cells are also thermogenic adipocyte cells that may be induced either pharmacologically or on account of cold to undergo browning.

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

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

In regards to the study

In the current study, researchers report that EPAC1 signaling might be pharmacologically and genetically manipulated for energy balance and to manage thermogenic progenitors. Mouse models were used to investigate the expression of Rapgef3 and Rapgef4 genes encoding EPAC1 and EPAC2, respectively, in various kinds of adipose tissues.

Energy expenditure was measured through oxygen consumption assessments conducted every 18 hours every 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, in addition to elucidate the role of EPAC1 within 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. Moreover, 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 grasp brown adipose tissue differentiation. Non-immortalized brown adipocytes were used to grasp proliferation using the 5-ethynyl-2′-deoxyuridine (EdU) assay.

High-sensitivity evaluation of phosphoproteomics was conducted to grasp 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 expansion of brown adipose tissue and browning of white adipose tissue, thereby leading to lower diet-induced obesity and increased expenditure of energy.

The proliferation of thermogenic adipocytes is controlled by a regulator network that’s coordinated by EPAC1; nonetheless, an analogous process doesn’t 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 doesn’t induce the proliferation of white adipocytes. This means a possible 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.


EPAC1 appears to play a major role in regulating the differentiation and proliferation of brown and beige adipocytes. Thus, this protein might be a possible goal for pharmacological activation to advertise brown and beige adipose tissue growth, improve cardiometabolic health, and increase energy expenditure. Moreover, the expansion of brown adipose tissue, the following increase in energy expenditure, and the secretion of protective endocrine aspects may be used to deal with metabolic diseases reminiscent of 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
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