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Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that increases with exercise and is thought to increase corticosterone and lipid utilization. How post-exercise nutrient availability impacts GDF15 and the physiological role that GDF15 plays during and/or in the recovery from exercise has not been elucidated. The purpose of this investigation was to examine how post-exercise nutrient availability impacts GDF15 and to use this as a model to explore associations between GDF15, corticosterone and indices of lipid and carbohydrate metabolism. In addition, we explored the causality of these relationships using GDF15 deficient mice. Male and female C57BL/6J mice ran for 2 hours on a treadmill and were sacrificed immediately or 3 hours after exercise with or without access to a chow diet. In both sexes, circulating concentrations of GDF15, corticosterone, non-esterified fatty acids (NEFA), and beta hydroxybutyrate (BHB) were higher immediately post-exercise and remained elevated when food was withheld during the recovery period. While serum GDF15 was positively associated with corticosterone, BHB and NEFA, increases in these factors were similar in wildtype and GDF15 -/- mice following exercise. The lack of a genotype effect was not explained by differences in insulin, glucagon or epinephrine after exercise. Our findings provide evidence that while GDF15 is associated with increases in corticosterone and indices of lipid utilization this is not a causal relationship.

Olanzapine is a second-generation antipsychotic (AP) used in the management of schizophrenia. Although effective at reducing psychoses, APs cause rapid hyperglycemia, insulin resistance, and dyslipidemia, an effect mediated in part by glucagon. We tested if amylin, a hormone that reduces glucagon, or the amylin receptor agonist pramlintide would protect against acute olanzapine-induced impairments in glucose and lipid homeostasis alone or in combination with other glucose-lowering agents such as liraglutide. We demonstrated that pramlintide lowered olanzapine-induced increases in glucagon:insulin ratio with a trend to protect against excursions in blood glucose. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia, which was mirrored by reductions in glucagon and attenuated markers of dyslipidemia. Our findings provide evidence that pramlintide, although moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance the protective effects of other interventions against acute olanzapine-induced metabolic dysfunction., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach. NEW & NOTEWORTHY Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.