Roles of Norepinephrine, Free Fatty Acids, Thyroid Status, and Skeletal Muscle Uncoupling Protein 3 Expression in Sympathomimetic-Induced Thermogenesis

Abstract

Thyroid hormone (TH) plays a fundamental role in thermoregulation, yet the molecular mediators of its effects are not fully defined. Recently, skeletal muscle (SKM) uncoupling protein (UCP) 3 was shown to be an important mediator of the thermogenic effects of the widely abused sympathomimetic agents 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) and methamphetamine. Expression of UCP3 is regulated by TH. Activation of UCP3 is indirectly regulated by norepinephrine (NE) and is dependent upon the availability of free fatty acids (FFAs). We hypothesized that UCP3 may be a molecular link between TH and hyperthermia, requiring increased levels of both NE and FFAs to accomplish the thermogenic effect. Here, we demonstrate that MDMA (40 mg/kg s.c.) significantly increases plasma FFA levels 30 min after treatment. Pharmacologically increasing NE levels through the inhibition of phenylethanolamine N-methyltransferase with Ϯ2,3-dichloro-␣-methylbenzylamine potentiated the hyperthermic effects of a 20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion according to levels of circulating plasma TH. Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression. Acute TH supplementation did not change the skeletal muscle UCP3 expression levels or temperature responses to MDMA. These findings suggest that, although MDMA-induced hyperthermia appears to result from increased NE and FFA levels, susceptibility is ultimately determined by TH regulation of UCP3-dependent thermogenesis.Hyperthermia results from a severe, unregulated rise in core body temperature induced by high ambient temperature, strenuous exercise, endocrinopathy, or drug exposure. To our knowledge, no drug treatment has been established through controlled trials as an efficacious therapy for conditions that involve severe hyperthermia, with the exception of malignant hyperthermia, which is effectively reversed with dantrolene (Blank and Boggs, 1993). The lack of therapeutic options for the management of hyperthermia probably results from an inadequate understanding of the basic molecular mechanisms of thermogenesis.The principal active thyroid hormone (TH) 3,5,3Ј-triiodo-Lthyronine is formed from the precursor 3,5,3Ј,5Ј-tetraiodothyronine (T 4 , thyroxine) by deiodinases present in various tissues (Bianco and Larsen, 2005). Although TH has been established as the primary endocrinologic regulator of body temperature (Silva, 2005) and facultative thermogenesis (FT) (for review see Lowell and Spiegelman, 2000), the mechanisms involved are complex and incompletely characterized. One family of genes regulated by TH (Gong et al., 1997) and believed to play a significant role in FT encodes for the mitochondrial uncoupling proteins (UCPs).UCPs "uncouple" free energy stored in the mitochondrial electrochemical p...

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

“…For example, increasing hypothalamic malonyl CoA has prominent effects on skeletal muscle mitochondrial biogenesis, elevating rates of mitochondrial fatty acid oxidation and uncoupling protein activity Wolfgang and Lane, 2008). However, increased uncoupling protein activity is associated with increased thermogenesis (Bouillaud et al, 1985;Gong et al, 1997;Hinz et al, 1999;Sprague et al, 2007), and it is unknown what the consequences would be for uncontrolled thermogenesis in obese humans. Furthermore, it will be difficult to find a practical solution for targeting these enzymes to increase malonyl CoA selectively in the hypothalamus.…”

3,4-Methylenedioxymethamphetamine- and 8-Hydroxy-2-di-n-propylamino-tetralin-Induced Hypothermia: Role and Location of 5-Hydroxytryptamine 1A Receptors

“…Even in studies in which MDMA causes hyperthermia, a transient initial period of hypothermia or a delay in the development of hyperthermia is often seen (Gordon et al, 1991;Malberg et al, 1996). To date few studies have addressed the mechanisms responsible for MDMA-induced hypothermia.The principal pharmacologic action of MDMA is facilitation of transmission at monoaminergic nerve terminals, causing the release of monoamines in the central nervous system and more specifically elevating extracellular levels of serotonin, dopamine, and norepinephrine (Rothman et al, 2001;Gough et al, 2002;Sprague et al, 2007), all of which have been implicated in hyperthermia induced by MDMA. The mechanisms behind hypothermia induced by MDMA are, however, largely unknown.…”

“…The principal pharmacologic action of MDMA is facilitation of transmission at monoaminergic nerve terminals, causing the release of monoamines in the central nervous system and more specifically elevating extracellular levels of serotonin, dopamine, and norepinephrine (Rothman et al, 2001;Gough et al, 2002;Sprague et al, 2007), all of which have been implicated in hyperthermia induced by MDMA. The mechanisms behind hypothermia induced by MDMA are, however, largely unknown.…”

Influence of thyroid hormones on 3,4-methylenedioxymethamphetamine-induced thermogenesis and reinforcing strength in monkeys

“…MDMA-induced thermogenesis in rodents is also thyroid hormone dependent (Sprague et al, 2003(Sprague et al, , 2007. Clinically, there is a case report suggesting that hyperthyroidism potentiated the hyperthermic effects of ecstasy (Martin et al, 2007).…”