Abstract
Background As cows transition from pregnancy to lactation,free fatty acids(FFA)are mobilized from adipose tissues(AT)through lipolysis to counter energy defiicits.In clinically healthy cows,lipolysis intensity is reduced through-out lactation;however,if FFA release exceeds tissue demands or the liver's metabolic capacity,lipid byproducts accumulate,increasing cows'risk of metabolic and infectious disease.Endocannabinoids(eCBs)and their congeners,N-acylethanolamines(NAEs),are lipid-based compounds that modulate metabolism and inflammation.Their syn-thesis and release depend upon the availability of FFA precursors and the abundance of synthesizing and degrading enzymes and transporters.Therefore,we hypothesized that eCB production and transcription of endocannabinoid system components are modulated by lipolysis pathways in adipocytes.To test this hypothesis,we stimulated canoni-cal(isoproterenol,1 μmol/L;ISO)and inflammatory(lipopolysaccharide,1 μg/mL;LPS)lipolysis pathways in adipo-cytes isolated from the AT of 5 Holstein dairy cows.Following,we assessed lipolysis intensity,adipocytes'release of eCBs,and transcription of endocannabinoid system components.Results We found that ISO and LPS stimulated lipolysis at comparable intensities.Exposure to either treat-ment tended to elevate the release of eCBs and NAEs by cultured adipocytes;however,specific eCBs and NAEs and the transcriptional profiles differed by treatment.On one hand,ISO enhanced adipocytes'release of 2-ara-chidonoylglycerol(2-AG)but reduced NAE production.Notably,ISO enhanced the cells'expression of enzymes associated with 2-AG biosynthesis(INPP5F,GDPD5,GPAT4),transport(CD36),and adipogenesis(PPARG).Conversely,LPS enhanced adipocytes'synthesis and release of N-arachidonoylethanolamide(AEA).This change coincided with enhanced transcription of the NAE-biosynthesizing enzyme,PTPN22,and adipocytes'transcription of genes related to eCB degradation(PTGS2,MGLL,CYP27B1).Furthermore,LPS enhanced adipocytes'transcription of eCB and NAE transporters(HSPA1A,SCP2)and the expression of the anti-adipogenic ion channel,TRPV3.Conclusions Our data provide evidence for distinct modulatory roles of canonical and inflammatory lipolysis pathways over eCB release and transcriptional regulation of biosynthesis,degradation,transport,and ECS signaling in cows'adipocytes.Based on our findings,we conclude that,within adipocytes,eCB production and ECS compo-nent expression are,at least in part,mediated by lipolysis in a pathway-dependent manner.These findings contrib-ute to a deeper understanding of the molecular mechanisms underlying metabolic regulation in dairy cows'AT,with potential implications for prevention and treatment of inflammatory and metabolic disorders.
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