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In multicellular organisms, signaling from the nervous system to the peripheral tissues can activate physiological responses to stress. Here, we show that inter-tissue stress communication can also function in reverse, i.e. from the peripheral tissue to the nervous system. <i>osm-8</i> mutants, which activate the osmotic stress response in the <i>C. elegans</i> skin, also exhibit defective osmotic avoidance behavior and an attenuated response of the ASH osmosensory neuron to hypertonic stimuli. Both <i>osm-8</i> and the Patched-related gene <i>ptr-23</i>, mutations in which suppress all <i>osm-8</i> phenotypes, function is the hypodermal lysosomes to regulate both physiology and behavior. Unbiased lipidomic analysis shows that <i>osm-8</i> leads to a <i>ptr-23</i>-dependent elevation of the lysosome specific lipid bis(monoacylglycero)phosphate (BMP) and expansion of the pool of hypodermal lysosomes. Just as genetic activation of the osmotic stress response by loss of <i>osm-8</i> in the hypodermis causes an Osm phenotype, acute physiological exposure to osmotic stress also confers a reversible Osm phenotype. Behavioral and genetic plasticity requires glycerol biosynthesis. However, ptr-23 is only required for osm-8 induced behavioral plasticity and not physiological plasticity. Instead, both genetic and physiologically induced Osm phenotypes require the unusual non-neuronal lysosomal V-ATPase subunit <i>vha-5</i>, which is also critical for organismal osmotic stress survival. Together, these data reveal that genetic or physiological activation of stress signaling from the skin elicits lysosome-associated signals that modulate organismal physiology to attenuate a sensory neuron circuit. Such ‘body-brain’ interoceptive communication may allow organisms to better match neuronal decision-making with organismal physiological state.