Metabolic Regulation of Lipid Signaling in Adipose Tissue

Adipose tissue operates as a dynamic endocrine organ, integrating nutrient status with systemic energy balance through specialised lipid mediators. Among these, branched-chain fatty acid esters of hydroxy fatty acids (FAHFAs) and related species have emerged as central signalling molecules that modulate insulin sensitivity, inflammation and glucose homeostasis. The regulation of these lipids depends on the coordinated action of biosynthetic enzymes, such as adipose triglyceride lipase (ATGL) acting via transacylation, and of hydrolytic enzymes, including the hydrolases AIG1 and ADTRP. Intracellular transcriptional programmes, notably those involving interferon regulatory factor 3 (IRF3), exert control over hydrolase expression and FAHFA turnover. Nutrient excess, immune inputs and changes in triglyceride pools influence the local availability of signalling lipids, shaping adipocyte function and cross-talk with macrophages. Disruption of this network contributes to chronic inflammation, insulin resistance and the progression of metabolic disease. Understanding the metabolic regulation of lipid signalling in adipose tissue therefore offers routes to novel therapeutic strategies aimed at restoring metabolic health.

Research from Nature Portfolio

Recent studies have delineated the IRF3–AIG1 axis as a critical link between inflammation and lipid-mediated insulin resistance. Activation of IRF3 in adipocytes upregulates AIG1, promoting hydrolysis of endogenous FAHFAs and impairing glucose homeostasis, whereas IRF3 or AIG1 inhibition restores insulin sensitivity under high-fat feeding. This work highlights how inflammatory transcription factors directly alter lipid-signalling pools in adipose tissue and identifies hydrolase inhibition as a potential therapeutic approach.

Another pivotal advance has been the discovery that ATGL possesses a transacylase activity that catalyses FAHFA biosynthesis by transferring fatty acids from triglycerides onto hydroxy fatty acids. Genetic or pharmacological modulation of ATGL in adipose tissue profoundly alters FAHFA levels, establishing this lipase as the first bona fide biosynthetic enzyme for these signalling lipids. This finding shifts the paradigm of ATGL function and underscores the metabolic interdependence of storage lipids and signalling molecules.

Earlier work established that levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) are diminished in dysfunctional human adipose tissue and correlate with expression of lipogenic enzymes and glucose transporter-4. Low PAHSA concentrations align with adipocyte hypertrophy and systemic insulin resistance, pointing to an endogenous lipid class that promotes healthy adipogenesis and metabolic resilience.

Metabolic Regulation of Lipid Signaling in Adipose Tissue publication trend

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

Technical terms

Branched-chain fatty acid esters of hydroxy fatty acids (FAHFAs): A class of endogenous lipids formed by esterification of a fatty acid to a hydroxy fatty acid, with roles in insulin sensitivity and inflammation.

Adipose triglyceride lipase (ATGL): A lipase that initiates triglyceride hydrolysis and, via a transacylase reaction, catalyses FAHFA biosynthesis in adipose tissue.

AIG1 (androgen-induced gene 1): A threonine hydrolase in adipocytes that degrades FAHFAs and links inflammatory signalling to metabolic dysfunction.

PAHSAs (palmitic acid esters of hydroxy stearic acids): A subset of FAHFAs with notable anti-diabetic and anti-inflammatory properties in adipose tissue.

Transacylation: A biochemical reaction transferring an acyl group from one lipid molecule (e.g. triglyceride) to another (e.g. hydroxy fatty acid) to form signalling lipids.

References

1. Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels. Nature Communications (2024).
2. AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice. Journal of Biological Chemistry (2020).
3. ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids. Nature (2022).
4. Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids. Scientific Reports (2018).
5. Distinct biological activities of isomers from several families of branched fatty acid esters of hydroxy fatty acids (FAHFAs). Journal of Lipid Research (2021).
6. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Are Associated With Diet, BMI, and Age. Frontiers in Nutrition (2021).