Adipocyte-Specific GH Receptor–Null (AdGHRKO) Mice Have Enhanced Insulin Sensitivity With Reduced Liver Triglycerides

List, Edward O.; Berryman, Darlene E.; Buchman, Mathew; Parker, Caitlin; Funk, Kevin; Bell, Stephen; Duran‐Ortiz, Silvana; Qian, Yanrong; Young, J. A.; Wilson, Christopher C.; Slyby, Julie; McKenna, Savannah; Jensen, Elizabeth; Kopchick, John J.

doi:10.1210/en.2018-00850

Cited by 40 publications

(38 citation statements)

References 45 publications

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“…Although comparable human clinical conditions do not exist, tissue-specific mouse lines also allow one to explore the role of GH in selected tissues and/or cell types. Relevant to adipose tissue, two separate adipose tissue-specific GHR gene disrupted or knockout (FaGHRKO and AdGHRKO) mouse lines have been characterized 99,100 . In addition, as the majority of circulating IGF1 is produced by hepatocytes, liver-specific GHR knockout (LiGHRKO) mice allows the evaluation of other tissues, including adipose tissue, under conditions of elevated GH and low IGF-1.…”

Section: Mouse Models With Altered Gh Activitymentioning

confidence: 99%

“…Interestingly, a 2018 study from our research group showed that GH action is positively correlated with ECM deposition. For example, bGH mice and LiGHRKO have excess fibrosis and collagen deposition in adipose tissue, whereas GHA, AdGHRKO and FaGHRKO mice (Table 1) have reduced collagen content 100,149 . This phenomenon is most prominent in the subcutaneous fat depot and correlated better with GH action rather than IGF1 action.…”

Section: Adipose Tissue Fibrosismentioning

confidence: 99%

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The effects of growth hormone on adipose tissue: old observations, new mechanisms

et al. 2019

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The ability of growth hormone (GH) to induce adipose tissue lipolysis has been known for over five decades; however, the molecular mechanisms that mediate this effect, as well as the ability of GH to inhibit insulin-stimulated glucose uptake, have been scarcely documented. In this same timeframe, our understanding of adipose tissue has evolved to reveal a complex structure with distinct types of adipocytes, depot-specific differences, a biologically significant extracellular matrix and important endocrine properties mediated by adipokines. All of these aforementioned features, in turn, can influence lipolysis. In this Review, we provide a historical and current overview of the lipolytic effect of GH in humans, mice and cultured cells. More globally, we explain lipolysis in terms of GH-induced intracellular signaling and its effect on obesity, insulin resistance and lipotoxicity. In this regard, findings that define molecular mechanisms by which GH induces lipolysis are described. Finally, data are presented for the differential effect of GH on specific adipose tissue depots and on distinct classes of metabolically active adipocytes. Together, these cellular, animal and human studies reveal novel cellular phenotypes and molecular pathways regulating the metabolic effects of GH on adipose tissue.

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Section: Mouse Models With Altered Gh Activitymentioning

confidence: 99%

Section: Adipose Tissue Fibrosismentioning

confidence: 99%

The effects of growth hormone on adipose tissue: old observations, new mechanisms

et al. 2019

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“…Meanwhile, GHR −/− mice display enhanced insulin sensitivity and improved glucose homeostasis, even when challenged with high-fat (HF) diet (Coschigano et al., 2000, Coschigano et al., 2003, Dominici et al., 2000). Apart from the global Ghr -null models, tissue- and cell-specific Ghr knockout in liver (Fan et al., 2009, List et al., 2014), muscle (Vijayakumar et al., 2012a, Vijayakumar et al., 2012b, Mavalli et al., 2010, List et al., 2015), adipose tissues (List et al., 2013, List et al., 2019), macrophage (Lu et al., 2013), cardiac (Jara et al., 2016), and islet β cell (Wu et al., 2011) have been generated in mice, which have provided detailed information on physiological functions of GH signaling in local tissues. Most of the tissue-specific Ghr knockout (KO) mice showed similarities to GHR −/− mice (Wu et al., 2011, Vijayakumar et al., 2012a, Vijayakumar et al., 2012b, List et al., 2013, List et al., 2014, Fan et al., 2009, Sun and Bartke, 2014).…”

Section: Introductionmentioning

confidence: 99%

Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis

Ran

Wang

et al. 2019

iScience

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Summary Growth hormone (GH) binds to its receptor (growth hormone receptor [GHR]) to exert its pleiotropic effects on growth and metabolism. Disrupted GH/GHR actions not only fail growth but also are involved in many metabolic disorders, as shown in murine models with global or tissue-specific Ghr deficiency and clinical observations. Here we constructed an adipose-specific Ghr knockout mouse model Ad-GHRKO and studied the metabolic adaptability of the mice when stressed by high-fat diet (HFD) or cold. We found that disruption of adipose Ghr accelerated dietary obesity but protected the liver from ectopic adiposity through free fatty acid trapping. The heat-producing brown adipose tissue burning and white adipose tissue browning induced by cold were slowed in the absence of adipose Ghr but were recovered after prolonged cold acclimation. We conclude that at the expense of excessive subcutaneous fat accumulation and lower emergent cold tolerance, down-tuning adipose GHR signaling emulates a healthy obesity situation which has metabolic advantages against HFD.

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“…Beta-adrenergic signaling is one of the pathways that regulates brown adipocyte proliferation 47 , 48 ; however, because the HPA axis is not mature in the new born mouse pups, it is unlikely that the proliferation of classical brown adipocytes is driven by beta-adrenergic signaling in the iBAT naive growth phase. Growth hormone (GH) and Insulin growth factor (IGF) signaling pathways are essential for postnatal development 49 , 50 , and disruption of IGF but not GH signaling in the adipose tissue results in severe iBAT paucity 51 , 52 , suggesting that IGF signaling may regulate the classical brown adipocytes proliferation during the iBAT naive growth phase. Future studies are secured to assess whether manipulating the IGF signaling affects the proliferation of classical brown adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Both proliferation and lipogenesis of brown adipocytes contribute to postnatal brown adipose tissue growth in mice

Negron

Ercan-Şençiçek

Freed

et al. 2020

Sci Rep

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Brown adipose tissue (BAT) is the primary non-shivering thermogenesis organ in mammals, which plays essential roles in maintaining the body temperature of infants. Although the development of BAT during embryogenesis has been well addressed in rodents, how BAT grows after birth remains unknown. Using mouse interscapular BAT (iBAT) as an example, we studied the cellular and molecular mechanisms that regulate postnatal BAT growth. By analyzing the developmental dynamics of brown adipocytes (BAs), we found that BAs size enlargement partially accounts for iBAT growth. By investigating the BAs cell cycle activities, we confirmed the presence of proliferative BAs in the neonatal mice. Two weeks after birth, most of the BAs exit cell cycle, and the further expansion of the BAT was mainly due to lipogenesis-mediated BAs volume increase. Microscopy and fluorescence-activated cell sorting analyses suggest that most BAs are mononuclear and diploid. Based on the developmental dynamics of brown adipocytes, we propose that the murine iBAT has two different growth phases between birth and weaning: increase of BAs size and number in the first two weeks, and BAs size enlargement thereafter. In summary, our data demonstrate that both lipogenesis and proliferation of BAs contribute to postnatal iBAT growth in mice.

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Adipocyte-Specific GH Receptor–Null (AdGHRKO) Mice Have Enhanced Insulin Sensitivity With Reduced Liver Triglycerides

Cited by 40 publications

References 45 publications

The effects of growth hormone on adipose tissue: old observations, new mechanisms

The effects of growth hormone on adipose tissue: old observations, new mechanisms

Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis

Both proliferation and lipogenesis of brown adipocytes contribute to postnatal brown adipose tissue growth in mice

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