Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

Lute, Beth; Jou, William; Lateef, Dalya M.; Goldgof, Margalit; Xiao, Cuiying; Piñol, Ramón A.; Kravitz, Alexxai V.; Miller, Nicole; Huang, Yuning; Girardet, Clémence; Butler, Andrew A.; Гаврилова, Оксана; Reitman, Marc L.

doi:10.1016/j.cmet.2014.05.021

Cited by 31 publications

(41 citation statements)

References 88 publications

(99 reference statements)

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“…Although we did not measure blood pressure, hypotension probably accompanies hypothermia because of the mast cell activation (Hannon et al, 1995). The hypotension may contribute to the hypothermia, but these can be dissociated [hypothermia without hypotension (Lute et al, 2014) and hypotension without hypothermia (Makabe-Kobayashi et al, 2002)]. …”

Section: Discussionmentioning

confidence: 98%

“…Indirect calorimetry was performed using an Oxymax/CLAMS (Columbus Instruments, Columbus, OH) at 22°C as described (Lute et al, 2014). Environmental temperature preference was measured using an in-house apparatus by continuous video monitoring of the position of the mouse in a 45-cm thermal gradient, nominally 18-36°C (Lute et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

“…Hypothermia, exemplified by hibernation and torpor, is also a physiologic mechanism used by small mammals to conserve energy (Geiser, 2004;Melvin and Andrews, 2009). Such endogenous hypothermia is actively achieved via disengaging brown adipose tissue, reducing physical activity and vasodilation, and seeking a cool environment (Heller and Ruby, 2004;Lute et al, 2014). Hypothermia can also be elicited pharmacologically by many drugs and neurotransmitters [e.g., Clark and Lipton (1985)].…”

Section: Introductionmentioning

confidence: 99%

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Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

Carlin

Tosh

Xiao

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Adenosine can induce hypothermia, as previously demonstrated for adenosine A 1 receptor (A 1 AR) agonists. Here we use the potent, specific A 3 AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A 3 AR. The hypothermic effect of A 3 AR agonists is independent of A 1 AR activation, as the effect was fully intact in mice lacking A 1 AR but abolished in mice lacking A 3 AR. A 3 AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A 3 AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brainpenetrant agonist caused hypothermia, suggesting that peripheral A 3 AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H 1 (but not H 2 or H 4 ) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A 3 AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A 3 AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H 1 receptors to induce hypothermia. This mechanism suggests that A 3 AR agonists will probably not be useful for clinical induction of hypothermia.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

Carlin

Tosh

Xiao

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…The latter seems to be independent of MC4Rs and possibly dependent on a similar biphasic effect on heart rate [190, 191]. BAT plays a crucial role in adaptive thermogenesis in response to diet or environmental challenges.…”

Section: Role In Energy Expenditurementioning

confidence: 99%

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

Hill

Faulkner²

2016

Neuroendocrinology

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Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient.

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“…3C). Since MTII used at 80μg/animal reaches the maximal effect on body temperature reduction in mice [21], this result suggests that MTII and 5′AMP showed a synergistic effect, suggesting a common pathway responsible for the two drugs. To further examine whether β-ARs are also involved in 5′AMP induced hypothermia, we used Beta-less mice.…”

Section: Resultsmentioning

confidence: 99%

Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists

Kim

Fan

et al. 2014

Biochemical and Biophysical Research Communications

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The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5′AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII’s effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature.

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Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

Cited by 31 publications

References 88 publications

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists

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