Administration of Thyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus of Male Rats Mimics the Metabolic Cold Defense Response

Zhi, Zhang; Machado, Frederico Sander Mansur; Zhao, Li; Heinen, Charlotte A; Foppen, Ewout; Ackermans, Mariëtte T.; Zhou, Jiang; Bisschop, Peter H.; Boelen, Anita; Fliers, Eric; Kalsbeek, Andries

doi:10.1159/000492785

Cited by 11 publications

(8 citation statements)

References 71 publications

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“…Therefore, in addition to hypophysiotropic TRH neurons involved in the endocrine response via the HPT axis, also nonhypophysiotropic TRH neurons in the PVN probably contribute to the cold response via an autonomic relay. The concept that TRH release in the PVN plays an important role in control of thermogenesis and energy mobilization during cold exposure was supported by recent observations in rats exposed to either cold or TRH microdialysis in the PVN for 2 h [21]. Cold exposure increased body temperature, locomotor activity, and plasma corticosterone concentrations, while blood glucose concentrations remained unchanged.…”

Section: Effects Of Trh On Bat Thermogenesismentioning

confidence: 82%

“…Interestingly, cold activates not only the hypophysiotropic TRH neurons that stimulate anterior pituitary TSH release but also the nonhypophysiotropic TRH neurons in the PVN [19, 20]. These nonhypophysiotropic TRH neurons project to various brain areas, exerting separate and diverse actions on energy homeostasis and BAT thermogenesis as described later on [13, 21]. …”

Section: Effects Of Cold Exposure On the Hpt Axismentioning

confidence: 99%

“…Further examination showed increased gluconeogenesis in the liver and lipolysis in BAT, both after cold exposure and after TRH administration. Thus, TRH administration in the PVN largely mimicked the metabolic and behavioral changes induced by cold exposure, indicating a potential link between TRH release in the PVN and cold defense [21]. …”

Section: Effects Of Trh On Bat Thermogenesismentioning

confidence: 99%

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TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

Zhi¹,

Boelen²,

Kalsbeek³

et al. 2018

Eur Thyroid J

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Thyroid hormone (TH) plays a key role in regulating body temperature in mammals. Cold exposure stimulates the hypothalamus-pituitary-thyroid (HPT) axis at the hypothalamic level by activating hypophysiotropic thyrotropin-releasing hormone (TRH)-producing neurons, ultimately resulting in increased plasma TH concentrations. Importantly, the local TH metabolism within various cold-responsive organs enables tissue-specific action of TH on heat production and adaption to cold independently of the circulating TH levels. In addition to these neuroendocrine effects, TRH neurons in the hypothalamus also have neural connections with brown adipose tissue (BAT), probably contributing to regulation of thermogenesis by the autonomic nervous system. Recent studies have demonstrated that intrahypothalamic TH has profound metabolic effects on BAT, the liver, and the heart that are mediated via the autonomic nervous system. These effects originate in various hypothalamic nuclei, including the paraventricular nucleus (PVN), the ventromedial nucleus, and recently reported neurons in the anterior hypothalamic area, indicating a potential central function for TH on thermoregulation. Finally, although robust stimulation of the thermogenic program in BAT was shown upon TH administration in the ventromedial hypothalamus, the physiological relevance of these neurally mediated effects of TH is unclear at present. This review provides an overview of studies reporting the role of TH in cold defense, with a focus on recent literature evidencing the centrally mediated effects of TRH and TH.

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Section: Effects Of Trh On Bat Thermogenesismentioning

confidence: 82%

Section: Effects Of Cold Exposure On the Hpt Axismentioning

confidence: 99%

Section: Effects Of Trh On Bat Thermogenesismentioning

confidence: 99%

See 1 more Smart Citation

TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

Zhi¹,

Boelen²,

Kalsbeek³

et al. 2018

Eur Thyroid J

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“…In support of this concept, intracerebroventricular administration of TRH induces both hyperthermia and transient hyperglycemia (Marubashi et al, 1988), whereas intracerebroventricular administration of a TRH antibody induces hypothermia (Prasad et al, 1980). Moreover, TRH-deficient mice exhibit cold intolerance and impaired glucose metabolism (Yamada et al, 1997), and TRH administration directly into the PVN increases thermogenesis, plasma corticosterone and blood glucose levels (Zhang et al, 2018). Lastly, POA cooling increases TSH release in conscious rats (Martelli et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Glucoregulatory responses to hypothalamic preoptic area cooling

et al. 2019

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Normal glucose homeostasis depends on the capacity of pancreatic β-cells to adjust insulin secretion in response to a change of tissue insulin sensitivity. In cold environments, for example, the dramatic increase of insulin sensitivity required to ensure a sufficient supply of glucose to thermogenic tissues is offset by a proportionate reduction of insulin secretion, such that overall glucose tolerance is preserved. That these cold-induced changes of insulin secretion and insulin sensitivity are dependent on the sympathetic nervous system (SNS) outflow suggests a key role for thermoregulatory neurons in the hypothalamic preoptic area (POA) in this metabolic response. As these POA neurons are themselves sensitive to changes in local hypothalamic temperature, we hypothesized that direct cooling of the POA would elicit the same glucoregulatory responses that we observed during cold exposure. To test this hypothesis, we used a thermode to cool the POA area, and found that as predicted, short-term (8-h) intense POA cooling reduced glucose-stimulated insulin secretion (GSIS), yet glucose tolerance remained unchanged due to an increase of insulin sensitivity. Longer-term (24-h), more moderate POA cooling, however, failed to inhibit GSIS and improved glucose tolerance, an effect associated with hyperthermia and activation of the hypothalamic-pituitary-adrenal axis, indicative of a stress response. Taken together, these findings suggest that POA cooling is sufficient to recapitulate key glucoregulatory responses to cold exposure.

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“…An efficient cold defense mechanism requires an accurate coordination of energy sources (e.g., glucose and fatty acids) and heat production (e.g., shivering and adaptive thermogenesis) [ 35 ]. Cold exposure increases food intake, leading to exogenous glucose supplementation in mice, which may have an effect on hepatic glucose metabolism [ 35 ]. In this study, the authors performed fasting treatment on experimental mice during cold exposure to avoid the effect of exogenous glucose.…”

Section: Discussionmentioning

confidence: 99%

Effects of Acute Cold Stress on Liver O-GlcNAcylation and Glycometabolism in Mice

Yao

Yang

Lian

et al. 2018

IJMS

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Protein O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) regulates many biological processes. Studies have shown that O-GlcNAc modification levels can increase during acute stress and suggested that this may contribute to the survival of the cell. This study investigated the possible effects of O-GlcNAcylation that regulate glucose metabolism, apoptosis, and autophagy in the liver after acute cold stress. Male C57BL/6 mice were exposed to cold conditions (4 °C) for 0, 2, 4, and 6 h, then their livers were extracted and the expression of proteins involved in glucose metabolism, apoptosis, and autophagy was determined. It was found that acute cold stress increased global O-GlcNAcylation and protein kinase B (AKT) phosphorylation levels. This was accompanied by significantly increased activation levels of the glucose metabolism regulators 160 kDa AKT substrate (AS160), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), and glycogen synthase kinase-3β (GSK3β). The levels of glycolytic intermediates, fructose-1,6-diphosphate (FDP) and pyruvic acid (PA), were found to show a brief increase followed by a sharp decrease. Additionally, adenosine triphosphate (ATP), as the main cellular energy source, had a sharp increase. Furthermore, the B-cell lymphoma 2(Bcl-2)/Bcl-2-associated X (Bax) ratio was found to increase, whereas cysteine-aspartic acid protease 3 (caspase-3) and light chain 3-II (LC3-II) levels were reduced after acute cold stress. Therefore, acute cold stress was found to increase O-GlcNAc modification levels, which may have resulted in the decrease of the essential processes of apoptosis and autophagy, promoting cell survival, while altering glycose transport, glycogen synthesis, and glycolysis in the liver.

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Administration of Thyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus of Male Rats Mimics the Metabolic Cold Defense Response

Cited by 11 publications

References 71 publications

TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

Glucoregulatory responses to hypothalamic preoptic area cooling

Effects of Acute Cold Stress on Liver O-GlcNAcylation and Glycometabolism in Mice

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