Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis

Lima, Juliana Bezerra Medeiros de; Debarba, Lucas Kniess; Khan, Manal M; Ubah, Chidera; Didyuk, Olesya; Ayyar, Iven; Koch, Madelynn; Sadagurski, Marianna

doi:10.1101/2020.08.17.254862

Cited by 3 publications

(3 citation statements)

References 44 publications

(55 reference statements)

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“…Interestingly, several lines of evidence have suggested an interaction between SIRT1 and GHR; however, the data are often contradictory [ 6 , 14 , 16 ]. To explore the colocalization between GHR-expressing neurons with SIRT1, we utilized our newly generated GHR tdtom mouse model [ 24 , 25 ]. The expression pattern of the tdTomato reporter reveals the presence of GHR-expressing neurons in the hypothalamus, as well as in other previously described brain sites [ 24 , 25 ].…”

Section: Resultsmentioning

confidence: 99%

“…To explore the colocalization between GHR-expressing neurons with SIRT1, we utilized our newly generated GHR tdtom mouse model [ 24 , 25 ]. The expression pattern of the tdTomato reporter reveals the presence of GHR-expressing neurons in the hypothalamus, as well as in other previously described brain sites [ 24 , 25 ]. We assessed the co-localization of SIRT1 with GHR-expressing neurons in fasting animals.…”

Section: Resultsmentioning

confidence: 99%

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Hypothalamic GHR—SIRT1 Axis in Fasting

Lima

Ubah

Debarba

et al. 2021

Cells

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Many aspects of physiological functions are controlled by the hypothalamus, a brain region that connects the neuroendocrine system to whole-body metabolism. Growth hormone (GH) and the GH receptor (GHR) are expressed in hypothalamic regions known to participate in the regulation of feeding and whole-body energy homeostasis. Sirtuin 1 (SIRT1) is the most conserved mamma-lian nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that plays a key role in controlling life span and sensing nutrient availability in the hypothalamus in response to caloric restriction. However, the interaction between GHR signaling and SIRT1 in the hypothal-amus is not established. In the arcuate nucleus (ARC) of the hypothalamus, the anorexigenic proopiomelanocortin (POMC)-expressing neurons and the orexigenic agouti-related protein (AgRP)-expressing neurons are the major regulators of feeding and energy expenditure. We show that in the ARC, the majority of GHR-expressing neurons also express SIRT1 and respond to fasting by upregulating SIRT1 expression. Accordingly, hypothalamic upregulation of SIRT1 in response to fasting is blunted in animals with GHR deletion in the AgRP neurons (AgRPEYFPΔGHR). Our data thus reveal a novel interaction between GH and SIRT1 in responses to fasting.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Hypothalamic GHR—SIRT1 Axis in Fasting

Lima

Ubah

Debarba

et al. 2021

Cells

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“…13 Additionally, using a novel GHR-Cre mouse model, a preprint study showed some co-localisation between GHR and TH in the ARH, although to a lower extent compared to the present study and with double-labelled cells located in the ventral ARH. 44 Thus, future studies should aim to determine the percentage of DAT or TH neurones that express GHR.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone receptor in dopaminergic neurones regulates stress‐induced prolactin release in male mice

Wasinski

Chaves

Pedroso

et al. 2021

J Neuroendocrinology

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Arcuate nucleus (ARH) dopaminergic neurones regulate several biological functions, including prolactin secretion and metabolism. These cells are responsive to growth hormone (GH), although it is still unknown whether GH action on ARH dopaminergic neurones is required to regulate different physiological aspects. Mice carrying specific deletion of GH receptor (GHR) in tyrosine hydroxylase (TH)‐ or dopamine transporter (DAT)‐expressing cells were produced. We investigated possible changes in energy balance, glucose homeostasis, fertility, pup survival and restraint stress‐induced prolactin release. GHR deletion in DAT‐ or TH‐expressing cells did not cause changes in food intake, energy expenditure, ambulatory activity, nutrient oxidation, glucose tolerance, insulin sensitivity and counter‐regulatory response to hypoglycaemia in male and female mice. In addition, GHR deletion in dopaminergic cells caused no gross effects on reproduction and pup survival. However, restraint stress‐induced prolactin release was significantly impaired in DAT‐ and TH‐specific GHR knockout male mice, as well as in pegvisomant‐treated wild‐type males, whereas an intact response was observed in females. Patch clamp recordings were performed in ARH DAT neurones and, in contrast to prolactin, GH did not cause acute changes in the electrical activity of DAT neurones. Furthermore, TH phosphorylation at Ser40 in ARH neurones and median eminence axonal terminals was not altered in DAT‐specific GHR knockout male mice during restraint stress. In conclusion, GH action in dopaminergic neurones is required for stress‐induced prolactin release in male mice, suggesting the existence of sex differences in the capacity of GHR signalling to affect prolactin secretion. The mechanism behind this regulation still needs to be identified.

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Hypothalamic Sex-Specific Metabolic Shift by Canagliflozin during Aging

Jayarathne,

Sullivan,

Stilgenbauer

et al. 2024

Preprint

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The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and promote metabolic homeostasis. Recent studies have shown that SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. We show that Cana treatment reduced body weight and fat mass in male mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that short-term Cana treatment (5 months) increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment (18 months) increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are impacted by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

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Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis

Cited by 3 publications

References 44 publications

Hypothalamic GHR—SIRT1 Axis in Fasting

Hypothalamic GHR—SIRT1 Axis in Fasting

Growth hormone receptor in dopaminergic neurones regulates stress‐induced prolactin release in male mice

Hypothalamic Sex-Specific Metabolic Shift by Canagliflozin during Aging

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