ABSTRACT
Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Gonads/metabolism , Longevity , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Signal Transduction , Trans-Activators/metabolism , Animals , Autophagy , Caenorhabditis elegans/genetics , Cell Nucleus/metabolism , Gene Expression Profiling , Gene Expression Regulation , Gene Knockdown Techniques , Germ Cells/metabolism , Protein Transport , ReproductionABSTRACT
Ceramides are bioactive sphingolipids, which are composed of sphingoid bases carrying acyl chains of various lengths. Ceramides are synthesized by a family of six ceramide synthases (CerS) in mammals, which produce ceramides with differentN-linked acyl chains. Increased ceramide levels are known to contribute to the development of obesity and insulin resistance. Recently, it has been demonstrated that the ceramide acylation pattern is of particular importance for an organism to maintain energy homeostasis. However, which of theCerSfamily members are involved in this process is not yet completely known. Using newly developedCerS5knock-out mice, we show here thatCerS5is essential to maintain cellular C16:0sphingolipid pools in lung, spleen, muscle, liver, and white adipose tissue. Glycerophospholipid levels inCerS5-deficient mice were not altered. We found a strong impact of CerS5-dependent ceramide synthesis in white adipose tissue after high fat diet feeding. In skeletal muscle, liver, and spleen, C16:0-ceramide levels were altered independent of feeding conditions. The loss ofCerS5is associated with reduced weight gain and improved systemic health, including maintenance of glucose homeostasis and reduced white adipose tissue inflammation after high fat diet challenge. Our findings indicate that reduction of endogenous C16:0-ceramide by genetic inhibition ofCerS5is sufficient to ameliorate obesity and its comorbidities.
