Summary Our previous study of patients with multiple symmetric lipomatosis (MSL) has identified their lack of response to major lipid mobilizing stimuli, as to fasting and noradrenaline infusion in vivo . Correspondingly, in vitro lipomatous tissue showed specific insensitivity to the lipolytic message of catecholamines, whereas it responded with marked lipomobilization to theophylline and to dibutyryl cyclic AMP. Cellular ATP levels were quite similar in lipomatous and in normal subcutaneous adipose tissue. Within the sequence of the lipolytic cascade, these observations indicated that the altered characteristic in MSL precede the activation of protein kinase. Correspondingly, the following possibilitics were considered : a) intercellular architecture, such as one rendering the diseased tissue inaccessible to catecholamines; b) predominance of alpha adrenergic receptors with inhibitory effect on lipolysis; c) a higher than normal phosphodiesterase activity in the subcutaneous tissue; d) a loss of beta adrenergic receptors or of adenylate cyclase function in lipomatous tissue. Catecholamine effect was studied in free lipomatous cells and in tissue fragments, the latter treated with the alpha blocking agent phentolamine. Phosphodiesterase activity, both soluble and particulate, was evaluated in normal as well as in pathological tissue. Adrenergic stimulation of free cells isolated from the lipoma does not elicit lipolysis. This insensitivity to adrenergic stimulation closely parallels that found earlier in tissue samples. Phentolamine does not modify the response to adrenaline in lipomatous tissue. The latter contains as much total phosphodiesterase (soluble plus particulate) as does the normal control. Finally, cholera toxin, an effective activator of adenylate cyclase, induces marked, dose dependent lipolytic response subsequent to a “lag period” of at least five hrs of preincubation. Thus, on the whole, in lipomatous tissue the defect in adrenergic lipomobilization is at the membrane level and may be attributed to a loss of beta-receptors or of some component function involved in coupling the beta-receptor to the adenylate cyclase activation so that pathological cells possess essentially no functional beta-receptors.