May 21, 2010 | Albaugh & et al.
This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague–Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition.
The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.
Collectively, the present study presents novel data related to the mechanism of a metabolic side effect of olanzapine observed in humans, i.e. FFA lowering. It has also shown that acute olanzapine induces metabolic inflexibility by causing a rapid shift in the major fuel being oxidized within peripheral tissues from mostly carbohydrate to mostly fat while insidiously preventing the mobilization of that fuel. After food deprivation, and perhaps by extension between meals, these actions of olanzapine more rapidly deplete lipid fuel than would otherwise occur. The shift in fuel utilization appears to precede the development of insulin resistance and, therefore, has the potential to explain its development and conceivably may also be involved in some of the other known side effects of these drugs.