Cells adapt to temperature shifts by adjusting levels of lipid desaturation and membrane fluidity. heat adaptation by linking temperature shifts to regulation of lipid desaturase levels and membrane fluidity via an unprecedented mode of fatty acid signaling. Introduction How cells respond to changes in temperature is a fundamental PKC (19-36) issue in biology (de Mendoza 2014 Jordt et al. 2003 Sengupta and Garrity 2013 Changes in ambient temperature affect nearly all cellular and biochemical processes and drive adaptive responses to maintain cellular homeostasis. For example up- or down-shifts in temperature increase or decrease the fluidity of the cytoplasmic membrane respectively. To maintain membrane fluidity within an optimal range for normal biological activity lipid desaturases in the cell convert saturated fatty acids into unsaturated fatty acids to increase lipid desaturation and thus membrane fluidity in response to temperature downshifts (de Mendoza 2014 Flowers and Ntambi 2008 Holthuis and Menon 2014 Nakamura and Nara 2004 Zhang and Rock 2008 Unsaturated IKBKB double bonds in lipids generate kinks into the otherwise straightened acyl hydrocarbon chain and thereby increase membrane fluidity. This PKC (19-36) fundamental process of maintaining membrane fluidity is called PKC (19-36) homeoviscous adaptation (HVA) and occurs in bacteria archaea and eukaryotes (Anderson et al. 1981 Cossins and Prosser 1978 Shmeeda et al. 2002 Sinensky 1974 A two-component regulatory system mediates HVA in bacteria (Aguilar et al. 2001 de Mendoza 2014 Holthuis and Menon 2014 Zhang and Rock 2008 In gene which encodes a lipid desaturase Des. This induction is controlled by the DesK-DesR two-component system: upon temperature down-shift the transmembrane histidine kinase DesK phosphorylates and activates the response regulator DesR which stimulates transcription of at low temperatures. Whether regulation of lipid desaturation by this pathway is involved in heat adaptation remains unclear. Furthermore neither DesK nor DesR has apparent homologs in eukaryotes and specific biological pathways leading to lipid desaturase regulation and HVA in eukaryotes remain unknown. The nematode is an ectotherm i.e. its body temperature depends on external sources. survives and reproduces optimally over an environmental temperature range of 15°C and 25°C. Temperatures beyond this range cause physiological stress reduction of fecundity tissue damage and necrosis (Kourtis et al. 2012 van Oosten-Hawle and Morimoto 2014 Previous studies of thermoregulation have focused on understanding how the heat-shock transcription factor HSF-1 functions to maintain proteostasis and cytoskeletal integrity (Baird et al. 2014 van Oosten-Hawle and Morimoto 2014 van Oosten-Hawle et al. 2013 and on sensory neural circuits and thermotaxis behavioral strategies that PKC (19-36) allow the animal to navigate a temperature gradient (Garrity et al. 2010 Hedgecock and Russell 1975 Mori and Ohshima 1995 Sengupta and Garrity 2013 Although the genome encodes seven lipid desaturases that are evolutionarily conserved and involved in fatty acid regulation (Brock et al. 2006 Watts 2009 the functions and mechanisms of HVA in have not been explored. We identified the gene (acyl-CoA-dehydrogenase) from a genetic screen exploring how this animal responds to conditions of changing oxygen and subsequently discovered that functions in HVA and does so by regulating levels of the stearic Co-A desaturase (SCD) FAT-7. encodes a member of the evolutionarily conserved ACDH family which is broadly involved in lipid β-oxidation. To understand the mechanism of action of ACDH-11 we solved its high-resolution crystal structure. This structure helped us establish that ACDH-11 inhibits expression by sequestering C11/C12-chain fatty acids and preventing them from activating expression mediated by the nuclear hormone receptor (NHR) NHR-49 a homolog of the mammalian fatty acid-binding transcription factors HNF4α and PKC (19-36) PPARα (Antebi 2006 Ashrafi 2007 Atherton et al. 2008 Evans and Mangelsdorf 2014 Van Gilst et al. 2005 PKC (19-36) Our findings demonstrate that specific intracellular fatty acids link ACDH-11 in a metabolic pathway to NHRs for transcriptional control.