Glucocorticoid Receptor‐mediated Lipolysis Increases following Chronic Adrenocorticotropin Infusion in Northern Elephant Seals Pups through its Imperative Interaction with Heat Shock 90 Chaperone Protein

Abstract

Northern elephant seal (NES) pups experience a prolonged 2–3 month fasting period and rely primarily on the oxidation of fatty acids to meet its energetic needs. Heat shock 90 chaperone protein (HSP90) is a fundamental part of the glucocorticoid‐cortisol (GR) complex, inducing an up regulation in GR‐mediated lipolysis upon chronoic adrenocorticotropin infusion. This fast is characterized by an increase in cortisol, HSP 90 and non‐esterified fatty acids (NEFA's). However, the functional relevance of this increase in cortisol via the GR is not well defined. We hypothesized that ACTH infusion increases lipolysis in NES. The contributions of cortisol and its receptor (GR) were assessed by exogenous infusion of ACTH and/or concurrently blocking the glucocorticoid receptor in the following groups: 1) control (no treatment), 2) ACTH (40 units of ACTH gel), 3) GR‐blocker (400mg mifepristone in time release pellets), and 4) ACTH+GR‐blocker. Plasma and adipose biopsy samples were collected at days 0 (T0; immediately prior to infusion) and 6 (T6). Mean plasma cortisol concentrations decreased 41±5% in the ACTH‐infused group and 21±3% in the combo group, but remained constant in the control and GR‐blocker groups suggestive of adrenal exhaustion. In contrast, mean plasma aldosterone increased 135%± 4 in the ACTH‐infused group suggesting that the adrenal gland in NES pups is differentially responsive (zona fasciculata vs zona glomerulosa). Mean NEFA levels increased 38%±4 in the ACTH‐infused group suggesting that ACTH‐mediated effects contribute to increased lipolysis. Mean heat shock protein 90 levels increased 119±1 in the ACTH infused group, 31±3 in the GR‐blocker and 192± 4 in the ACTH+GR‐Blocker group suggesting that mifepristone has no residual effect on the binding of HSP90 to the glucocorticoid receptor, making this interaction imperative in GR‐mediated lipolysis. Collectively, this data suggests that the fasting‐associated increase in cortisol is an important contributing factor in stimulating lipolysis potentially through the glucocorticoid receptor.