Objective: To determine whether key appetite‐regulating neuropeptides such as melanin‐concentrating hormone (MCH), neuropeptide Y (NPY), and α‐melanocyte—stimulating hormone (α‐MSH), which are known to mediate energy balance through centrally mediated pathways, also have direct acute effects on the lipolytic activity of murine adipocytes.

Research Methods and Procedures: Fully differentiated 3T3‐L1 adipocytes serum starved overnight in Dulbecco's modified Eagle medium containing 2% bovine serum albumin or freshly isolated mouse adipocytes were incubated for up to 2 hours in the absence and presence of 100 nM each of NPY, MCH, α‐MSH, the melanocortin receptor agonist MTII, or isoproterenol as a control. Free fatty acids secreted into the incubation medium were measured using a commercially available nonesterified fatty acid C test kit.

Results: Treatment of 3T3‐L1 cells with 100 nM NPY decreased basal free fatty acid secretion (basal, 0.006 ± 0.001 vs. NPY, 0.001 ± 0.0003 nM at 90 minutes; p < 0.05), whereas both α‐MSH and MTII stimulated up to a 7‐fold increase in free fatty acid release (MTII, 0.238 ± 0.004 vs. basal, 0.024 ± 0.002 nM at 2 hours; p < 0.05; and α‐MSH, 0.22 ± 0.005 vs. basal, 0.04 ± 0.003 nM at 2 hours; p < 0.05). Treatment with 100 nM MCH had no effect on basal free fatty acid release or on α‐MSH—induced lipolysis during concurrent treatment. Conversely, concurrent treatment with 100 nM NPY dramatically inhibited (by ∼90%) α‐MSH—induced lipolysis. Similar treatment of freshly isolated mouse adipocytes showed virtually identical results.

Discussion: In addition to their centrally mediated actions, appetite‐regulating neuropeptides modulate adipose tissue mass through direct peripheral effects. Systemic administration of pharmacological agents altering the effects of these neuropeptides may form the basis of future obesity therapies. Thus, some of these agents will likely have direct effects on adipocytes that may serve to alter their therapeutic effectiveness.