Three areas of research on hormonal control of adipocyte metabolism are summarized: (A) Previously, we reported the discovery of several species of hormonally regulated, lipid storage droplet-associated phosphoproteins (LAPP). Protease digestion and peptide mapping of four LAPPs confirms that they are phosphorylation variants of a single polypeptide. Western blot scans of rat tissues with an affinity-purified antibody raised against LAPP indicates that it is adipose cell-specific. Finally, immunocytochemical studies with 3T3-L1 adipocytes reveals that LAPP is tightly associated with the lipid droplet surface in intact cells. (B) Extending our finding that insulin rapidly activates protein kinase C activity in adipocytes, we find that insulin also stimulates the breakdown of the an inositol phospholipid, leading to release of IP3(1,4,5), the calcium-releasing metabolite. IP3 formation peaks within seconds of exposure of cells to physiological insulin concentrations, concomitant with increased phosphorylation of a specific isoform of phospholipase C, a potential target for the insulin receptor tyrosine kinase activity. Interestingly, comparative studies of inositol phosphate metabolites formed with insulin and vasopressin indicate that insulin-stimulated hydrolysis of inositolphospholipids may proceed through a hitherto undescribed pathway. (C) Cachectic patients exhibit high concentrations of plasma Interleukin-6 (IL-6), and we have found that IL-6 acts directly on both freshly isolated adipocytes and on cultured 3T3-Ll adipocytes to decrease lipoprotein lipase (LPL) activity. We now find that adipocytes isolated from animals administered IL-6 possess greatly reduced LPL activity, providing further support for the notion that IL-6 may play a role in cachexia. A potentially related finding is that factors that stimulate the differentiation of precursor 3T3-L1 fibroblasts into adipocytes strongly inhibit IL-6 production by the precursor cells. Finally, on the matter of cytokine effects on adipose cells, we find elevated levels of interferons in sera of subjects with lipoatrophy, a syndrome characterized by an inability to store fat. Taken together, these observations strongly suggest a pathophysiological role for cytokines in a number of diseases manifested by abnormal lipid storage.
