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Growth Hormone Receptor bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254862; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 2 3 4 Growth hormone receptor (GHR)-expressing neurons in the 5 hypothalamic arcuate nucleus regulate glucose metabolism and energy 6 homeostasis 7 8 9 10 11 12 Juliana Bezerra Medeiros de Lima, Lucas Kniess Debarba, Manal Khan, Chidera Ubah, 13 Olesya Didyuk, Iven Ayyar, Madelynn Koch, and Marianna Sadagurski 14 15 16 17 18 Department of Biological Sciences, Integrative Biosciences Center (IBio), Wayne State 19 University, Detroit, Michigan, MI 20 21 22 23 24 25 26 27 Corresponding author: 28 Marianna Sadagurski, 29 Department of Biological Sciences, 30 Integrative Biosciences Center 31 Wayne State University 32 Room 2418 IBio, 33 6135 Woodward, Detroit, MI 48202 34 Phone: (313) 577 8637 35 Email: [email protected] 36 37 38 Competing Interests Statement: The authors declare no competing interests. bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254862; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 39 Abbreviations 40 CNS, central nervous system; GH, growth hormone; GHR, growth hormone receptor; STAT5, 41 signal transducer and activator of transcription 5; POMC, proopiomelanocortin; ARC, arcuate nucleus 42 of the hypothalamus; DMH, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamus; PVH, 43 paraventricular hypothalamic nucleus; SST, somatostatin; GHRH, growth hormone releasing 44 hormone; AgRP, agouti-related peptide 45 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254862; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 46 Abstract48T 47 Growth hormone (GH) receptor (GHR), expressed in different brain regions, is known to 48 participate in the regulation of whole-body energy homeostasis and glucose metabolism. However, 49 GH activation of these GHR-expressing neurons is less studied. We have generated a novel GHR- 50 driven Cre recombinase transgenic mouse line (GHRcre) in combination with the floxed tdTomato 51 reporter mouse line we tracked and activated GHR-expressing neurons in different regions of the 52 brain. We focused on neurons of the hypothalamic arcuate nucleus (ARC) where GHR was shown to 53 elicit a negative feedback loop that regulates GH production. We found that ARCGHR+ neurons are co- 54 localized with AgRP, GHRH, and somatostatin neurons, which were activated by GH stimulation. 55 Using designer receptors exclusively activated by designer drugs (DREADDs) to control GHRARC 56 neuronal activity, we revealed that activation of GHRARC neurons was sufficient in regulating distinct 57 aspects of energy balance and glucose metabolism. Overall, our study provides a novel mouse model 58 to study in vivo regulation and physiological function of GHR-expressing neurons in various brain 59 regions. Furthermore, we identified for the first time specific neuronal population that responds to GH 60 and directly linked it to metabolic responses in vivo. 61 62 63 64 65 66 67 68 69 70 71 72 73 74 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254862; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 75 Introduction 76 A cumulative body of evidence established that growth hormone (GH) plays pivotal roles in 77 the regulation of systemic metabolism, through activation of the GH receptor (GHR) in the liver, 78 muscle, adipose, and other tissues (1-6). In the central nervous system (CNS), GH is present in 79 regions known to participate in the regulation of feeding, energy balance, and glucose metabolism, 80 including the hypothalamus, hippocampus, and amygdala (7-11). The expression of GHR within the 81 CNS has been mapped by in situ hybridization and by detection of the downstream target, the 82 phosphorylated activator of transcription (STAT) 5, revealing large numbers of GH-responsive 83 neurons in various brain regions (8,12,13). While these studies detected GHR expression within the 84 CNS, the functional assessment of the GHR-expressing neurons in various brain regions was lacking. 85 GHR expression in the brain is critical for the neuroendocrine neurons to sense and regulate 86 GH production by the pituitary (8,14,15). In the arcuate nucleus of the hypothalamus (ARC), the GHR 87 is involved in a negative feedback loop that regulates GH production and secretion by GH-releasing 88 hormone (GHRH) (8). As part of this negative feedback, GH inhibits it’s own secretion acting on the 89 GHR in neuropeptide Y (NPY) neurons in the ARC and somatostatin (SST) neurons in the 90 paraventricular nucleus (PVN). Activation of these neurons augments SST release and inhibits GH 91 secretion (16,17). In recent years, it became clear that GH action in the ARC represents an important 92 component of energy homeostasis (13). We have recently shown that neuronal-specific deletion of 93 GHR in leptin receptor (LepRb)-expressing neurons in the hypothalamus impaired hepatic glucose 94 production and systemic lipid metabolism (18). Additionally, mice lacking GHR specifically in the 95 orexigenic agouti-related peptide (AgRP) expressing neurons in the ARC display impaired responses 96 to fasting and food restriction, while deletion of GHR from anorexigenic proopiomelanocortin (POMC) 97 neurons in the ARC did not produce significant metabolic phenotype (19,20). Collectively, these 98 results indicated unique roles of GHR-expressing neurons in the ARC in metabolic control. However, 99 in vivo GH-mediated activation of GHR-expressing neurons were not studied. 100 In the current study, we specifically aimed at studying in vivo activation of these complex 101 neural circuitry of the GHR-expressing neurons in the ARC. To that end, we developed a novel GHR- bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254862; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 102 driven cre mouse (GHRcre) using the CRISPR/Cas9 gene-editing technology. The new GHRcre model 103 allowed us to both track and activate GHR-expressing neurons. Utilizing these mice, we studied the 104 functional roles of GHR neurons in the ARC in the regulation of systemic glucose metabolism and 105 energy homeostasis. We found that activation of GHRARC neurons acutely increased systemic glucose 106 sensitivity, energy expenditure, and heat production. Overall, our study revealed a novel network of 107 metabolic regulation through the hypothalamic GH axis in the ARC. Finally, our mouse model provides 108 a novel tool to identify specific neuronal populations mediating the effects of GH in different brain 109 regions. 110 111 112 113 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254862; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 114 Materials and Methods 115 116 Experimental Animals: 117 GHRcre mice were generated using the Clustered Regularly Interspaced Short Palindromic 118 Repeats associated protein Cas9 (CRISPR/Cas9) technology (21,22). All procedures were performed 119 at the University of Michigan Transgenic Core as before (22). A detailed description of the procedures 120 is described in Supplementary Materials and Methods. tdTomato mice on the ROSA26 background m14(CAG-tdTomato)Hze 121 (B6.Cg-Gt(ROSA)26SortP /J,P (stock 007914) were purchased from The Jackson 122 Laboratory. Adult male mice (8-12 weeks old) were used for all studies. All mice were provided 19Tad 123 libitum 19T access to standard chow diet (Purina Lab Diet 5001) and housed in temperature-controlled 124 rooms on a 12-hour/12-hour light-dark cycle. Mice were bred and housed within our colony according 125 to guidelines approved by the Wayne State University Committee on the Care and Use of Animals. 126 127 Perfusion and Histology: 128 Mice were anesthetized (IP) with avertin and transcardially perfused with phosphate-buffered 129 saline (PBS) (pH 7.5) followed by 4% paraformaldehyde (PFA). Brains were post-fixed, sank in 30% 130 sucrose, frozen in OCT medium, and then sectioned coronally (30 µm) and processed for 131 immunohistochemistry as previously described (23,24). For immunohistochemistry, free-floating 132 brain sections were washed in PBS, blocked using 3% normal donkey serum (NDS) and 0.3% Triton 133 X-100 in PBS and then stained with a primary antibody for 48 hours at 4°C with agitation in blocking 134 buffer: DsRed (anti-rabbit, 1:5000, cat. number NC9580775, Takara), GFP (anti-chicken, 1:1000, cat. 135 number ab13970, Abcam), anti-tdTom (anti-goat, 1:500, cat. number AB8181-200, Scigen), pSTAT5 136 (anti-rabbit, 1:500, cat.
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