Cyclic Nucleotide Signaling in Adipose Tissue Metabolism

Cyclic nucleotides such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) serve as central second messengers in adipose tissue, orchestrating the balance between energy storage and expenditure. Activation of adenylate cyclase raises intracellular cAMP, which stimulates protein kinase A (PKA) to promote lipolysis and initiate the thermogenic programme in brown and beige adipocytes. By contrast, synthesis of cGMP via guanylyl cyclases engages protein kinase G (PKG) to enhance mitochondrial activity and heat generation. Phosphodiesterases (PDEs) terminate these signals by degrading cyclic nucleotides, thereby fine-tuning adipocyte responses. Through coordinated regulation of lipolysis, mitochondrial biogenesis and inflammatory pathways, cyclic nucleotide signalling determines adipose plasticity, systemic glucose homeostasis and resistance to diet-induced obesity.

Research from Nature Portfolio

Recent studies have shown that pharmacological stimulation of soluble guanylyl cyclase enhances cGMP production in brown adipocytes, driving lipid uptake and energy expenditure to protect against weight gain. Genetic inactivation of phosphodiesterase 3B in mice elevates cAMP levels in white depots, activating PKA and AMP-activated protein kinase (AMPK) cascades to induce beige adipocyte formation, increase fatty acid oxidation and improve metabolic resilience under high-fat feeding. Further work has revealed that loss of PDE3B also restrains NLRP3 inflammasome assembly in white adipose tissue, reducing proinflammatory cytokine release, ameliorating insulin resistance and lowering atherosclerotic risk.

Cyclic Nucleotide Signaling in Adipose Tissue Metabolism publication trend

The graph below shows the total number of articles in cyclic nucleotide signaling in adipose tissue metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

cAMP: Cyclic adenosine monophosphate, a second messenger that activates protein kinase A to regulate lipolysis and thermogenesis.

cGMP: Cyclic guanosine monophosphate, a second messenger produced by guanylyl cyclases to control protein kinase G and metabolic processes.

Phosphodiesterase (PDE): Enzymes that hydrolyse cAMP or cGMP, terminating cyclic nucleotide signalling.

Brown Adipose Tissue (BAT): A fat depot specialised in heat production through mitochondrial uncoupling.

Browning: The emergence of thermogenic beige adipocytes within white fat under specific stimuli.

Soluble Guanylyl Cyclase (sGC): A haem-dependent enzyme that synthesises cGMP in response to nitric oxide.

AMP-activated Protein Kinase (AMPK): A cellular energy sensor that promotes fatty acid oxidation and mitochondrial biogenesis.

References

1. Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. Nature Communications (2015).
2. White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function. Scientific Reports (2017).
3. Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue. Scientific Reports (2016).
4. Fat tissues, the brite and the dark sides. Pflügers Archiv - European Journal of Physiology (2016).
5. A novel thermoregulatory role for PDE10A in mouse and human adipocytes. EMBO Molecular Medicine (2016).
6. Effects of sildenafil treatment on thermogenesis and glucose homeostasis in diet-induced obese mice. Nutrition & Diabetes (2018).