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Impact of Growth Hormone on Regulation of Adipose Tissue

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ABSTRACT

Increasing prevalence of obesity and obesity‐related conditions worldwide has necessitated a more thorough understanding of adipose tissue (AT) and expanded the scope of research in this field. AT is now understood to be far more complex and dynamic than previously thought, which has also fueled research to reevaluate how hormones, such as growth hormone (GH), alter the tissue. In this review, we will introduce properties of AT important for understanding how GH alters the tissue, such as anatomical location of depots and adipokine output. We will provide an overview of GH structure and function and define several human conditions and cognate mouse lines with extremes in GH action that have helped shape our understanding of GH and AT. A detailed discussion of the GH/AT relationship will be included that addresses adipokine production, immune cell populations, lipid metabolism, senescence, differentiation, and fibrosis, as well as brown AT and beiging of white AT. A brief overview of how GH levels are altered in an obese state, and the efficacy of GH as a therapeutic option to manage obesity will be given. As we will reveal, the effects of GH on AT are numerous, dynamic and depot‐dependent. © 2017 American Physiological Society. Compr Physiol 7:819‐840, 2017.

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Figure 1. Figure 1. AT depots in mice. Locations and classifications of four major WAT depots in a male mouse are shown on the left image. Mesenteric fat (top left) runs along the intestines and is, by strictest definition, a true visceral depot. The inguinal fat pad (bottom left) is classified as subQ and resides just beneath the skin. The epididymal depot (bottom right) is located next to the testes and has been moved outside of the abdominal space for better visualization. While epididymal fat is given an intra‐abdominal (IA) designation and sometimes referred to as visceral, many do not consider it a true visceral depot due to lack of drainage into the portal vein. The retroperitoneal depot (top right) is also visible, located behind the kidney (K). The location of the interscapular BAT depot is shown on the right. This is the only dissectible BAT fat pad in mice. Figure on the left was adapted from Sackmann‐Sala et al. () and reused from Berryman et al. () with permission.
Figure 2. Figure 2. AT depots in humans. Several prominent human AT depots are illustrated. Subcutaneous depots include gluteal, femoral, and two distinct abdominal fat pads, one superficial and one deep. Intraabdominal depots in humans include intraperitoneal, also known as visceral, and retroperitoneal AT. Perinephric fat surrounds the kidney, and retroperitoneal fat is located in the retroperitoneal space behind the kidneys. Visceral depots in humans line organs of the digestive system and include mesenteric and omental AT. Reused with permission from Lee et al. ().
Figure 3. Figure 3. Changes accompanying pathological WAT expansion in obesity. Expansion of healthy WAT (left) mainly occurs through adipocyte hyperplasia. At this stage, the tissue exists in an anti‐inflammatory state, characterized by higher levels of M2 macrophage populations as well as T regulatory cells and T helper cells. The ECM remains loose, allowing for unhindered tissue expansion. Vascularization is also adequate to support the tissue. Conversely, pathological expansion, as seen in obesity (right), favors hypertrophy of adipocytes and exhibits a pro‐inflammatory profile, hallmarked by increased infiltration of M1 macrophages, cytotoxic T cells, and natural killer cells, with decreased T regulatory cells and T helper cells. Expression of pro‐inflammatory cytokines TNF‐α, IL‐6, and MCP‐1 are also increased in this state. The ECM becomes rigid and deposition increases, leading to a state of fibrosis. Vascularization is insufficient to support the growing tissue, which results in hypoxia and ultimately adipocyte death. Adapted with permission from ().
Figure 4. Figure 4. Regulation of pituitary GH. The hypothalamus secretes GHRH and somatostatin (SST), which stimulate and inhibit GH secretion, respectively. GH induced intracellular signaling via the GH receptor results in IGF‐1 production by target tissues, which acts, along with GH, to decrease GH secretion through feedback inhibition. Other factors such as estrogen, leptin, and free fatty acids (FFAs) also modulate GH secretion. Adapted with permission from ().
Figure 5. Figure 5. The intracellular signaling cascade of GHR in response to GH binding. The canonical pathway consists of GHR‐JAK2‐STAT5. Phosphorylation of STAT5 in response to GH activates STAT5, which regulates target gene transcription. GHR also signals through IRS to activate mTOR and through Src to activate ERK and JNK.
Figure 6. Figure 6. Mice with altered GH action in a C57BL/6J genetic background. From top to bottom: a wild‐type (WT) mouse, a bGH transgenic mouse with elevated levels of GH action, a GHA transgenic mouse with decreased levels of GH action and a GHR gene disrupted mouse with no GH action via the GHR. Reused with permission from ().
Figure 7. Figure 7. Comparison of body fat percentage over time in mice with altered GH action. Male and female bGH mice have greater body fat percent than WT controls earlier in life, a trend which begins to reverse at 4 and 6 months of age, respectively. Percent fat mass is greater in male and female GHA mice compared to controls at all‐time points measured and continues to increase throughout life. Male GHR−/− mice have markedly increased body fat percent compared to controls and appear to rapidly accumulate fat during the first 4 months of life. Increases in percent fat are also observed in female GHR−/− mice respective to controls, though the differences are not as dramatic. Select data presented from previously published works with permission from ().
Figure 8. Figure 8. Comparison of collagen staining in AT. SubQ AT from 6‐month‐old bGH, WT controls and GHR−/− mice stained with picrosirius red, a commonly used histological technique to visualize collagen in paraffin‐embedded tissue sections.


Figure 1. AT depots in mice. Locations and classifications of four major WAT depots in a male mouse are shown on the left image. Mesenteric fat (top left) runs along the intestines and is, by strictest definition, a true visceral depot. The inguinal fat pad (bottom left) is classified as subQ and resides just beneath the skin. The epididymal depot (bottom right) is located next to the testes and has been moved outside of the abdominal space for better visualization. While epididymal fat is given an intra‐abdominal (IA) designation and sometimes referred to as visceral, many do not consider it a true visceral depot due to lack of drainage into the portal vein. The retroperitoneal depot (top right) is also visible, located behind the kidney (K). The location of the interscapular BAT depot is shown on the right. This is the only dissectible BAT fat pad in mice. Figure on the left was adapted from Sackmann‐Sala et al. () and reused from Berryman et al. () with permission.


Figure 2. AT depots in humans. Several prominent human AT depots are illustrated. Subcutaneous depots include gluteal, femoral, and two distinct abdominal fat pads, one superficial and one deep. Intraabdominal depots in humans include intraperitoneal, also known as visceral, and retroperitoneal AT. Perinephric fat surrounds the kidney, and retroperitoneal fat is located in the retroperitoneal space behind the kidneys. Visceral depots in humans line organs of the digestive system and include mesenteric and omental AT. Reused with permission from Lee et al. ().


Figure 3. Changes accompanying pathological WAT expansion in obesity. Expansion of healthy WAT (left) mainly occurs through adipocyte hyperplasia. At this stage, the tissue exists in an anti‐inflammatory state, characterized by higher levels of M2 macrophage populations as well as T regulatory cells and T helper cells. The ECM remains loose, allowing for unhindered tissue expansion. Vascularization is also adequate to support the tissue. Conversely, pathological expansion, as seen in obesity (right), favors hypertrophy of adipocytes and exhibits a pro‐inflammatory profile, hallmarked by increased infiltration of M1 macrophages, cytotoxic T cells, and natural killer cells, with decreased T regulatory cells and T helper cells. Expression of pro‐inflammatory cytokines TNF‐α, IL‐6, and MCP‐1 are also increased in this state. The ECM becomes rigid and deposition increases, leading to a state of fibrosis. Vascularization is insufficient to support the growing tissue, which results in hypoxia and ultimately adipocyte death. Adapted with permission from ().


Figure 4. Regulation of pituitary GH. The hypothalamus secretes GHRH and somatostatin (SST), which stimulate and inhibit GH secretion, respectively. GH induced intracellular signaling via the GH receptor results in IGF‐1 production by target tissues, which acts, along with GH, to decrease GH secretion through feedback inhibition. Other factors such as estrogen, leptin, and free fatty acids (FFAs) also modulate GH secretion. Adapted with permission from ().


Figure 5. The intracellular signaling cascade of GHR in response to GH binding. The canonical pathway consists of GHR‐JAK2‐STAT5. Phosphorylation of STAT5 in response to GH activates STAT5, which regulates target gene transcription. GHR also signals through IRS to activate mTOR and through Src to activate ERK and JNK.


Figure 6. Mice with altered GH action in a C57BL/6J genetic background. From top to bottom: a wild‐type (WT) mouse, a bGH transgenic mouse with elevated levels of GH action, a GHA transgenic mouse with decreased levels of GH action and a GHR gene disrupted mouse with no GH action via the GHR. Reused with permission from ().


Figure 7. Comparison of body fat percentage over time in mice with altered GH action. Male and female bGH mice have greater body fat percent than WT controls earlier in life, a trend which begins to reverse at 4 and 6 months of age, respectively. Percent fat mass is greater in male and female GHA mice compared to controls at all‐time points measured and continues to increase throughout life. Male GHR−/− mice have markedly increased body fat percent compared to controls and appear to rapidly accumulate fat during the first 4 months of life. Increases in percent fat are also observed in female GHR−/− mice respective to controls, though the differences are not as dramatic. Select data presented from previously published works with permission from ().


Figure 8. Comparison of collagen staining in AT. SubQ AT from 6‐month‐old bGH, WT controls and GHR−/− mice stained with picrosirius red, a commonly used histological technique to visualize collagen in paraffin‐embedded tissue sections.
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Further Reading

Berryman DE, Henry B, Hjortebjerg R, List EO. Developments in our understanding of the effects of growth hormone on white adipose tissue: implications on the clinic. Expert Reviews in Endocrinology and Metabolism. 2016; 11(2): 197-207.

Ho KKY and Works GDC. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH research society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. European Journal of Endocrinology 157: 695-700, 2007.

Israel E, Attie KM, Bengtsson BA, Blethen SL, Blum W, Cameron F, Carel JC, Carlsson L, Chipman JJ, Christiansen JS, Clayton P, Clemmons DR, Cohen P, Drop S, Fujieda K, Ghigo E, Hintz RL, Ho K, Ilondo MM, Jasper H, Jesussek B, Kappelgaard AM, Laron Z, Lippe BM, Malozowski S, Mullis PE, de Munick-Keizer-Schrama S, Nishi Y, Parks JS, Phelps C, Ranke M, Robinson I, Rosenfeld RG, Rose S, Saenger P, Saggese G, Savage M, Shalet S, Sizonenko PC, Strasburger C, Tachibana K, Tanaka T, Thorner MO, Wikland KA, Zadik Z, and Soc GR. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society. J Clin Endocrinol Metab 85: 3990-3993, 2000.

 

 

Teaching Material

 

 

K. M. Troike, B. E. Henry, E. A. Jensen, J. A. Young, E. O. List, J. J. Kopchick, D. E. Berryman. Impact of Growth Hormone on Regulation of Adipose Tissue. Compr Physiol 7 2017, 819-840.

 

Didactic Synopsis



 

 

 

 

 

Major Teaching Points:

     

  1. Adipose tissue (AT) is a complex, dynamic endocrine organ that secretes and responds to various hormones and cytokines.
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  3. Growth hormone (GH) has a profound impact on AT.
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    1. In AT, GH acts to inhibit insulin action, decrease glucose uptake, stimulate lipolysis, and inhibit lipogenesis.
    2.  

       

    3. GH regulates other AT properties, such as endocrine output, immune cell function, senescence, differentiation, beiging, and extracellular matrix deposition.
    4.  

     

  5. Perturbations in GH-induced signaling are responsible for a number of clinical conditions (e.g., acromegaly, Laron Syndrome, and GH deficiency). Many genetically altered mouse lines have been developed to study these diseases.
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  7. The GH-IGF-1 axis plays a role in obesity.
  8.  

 

  1. GH secretory response is blunted in obesity.
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  3. Visceral WAT accumulation is negatively correlated with GH secretion.
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  5. Treatment of obesity using rhGH is not currently advised with additional studies needed to demonstrate its safety and efficacy.
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Didactic Legends

 


 

 

 

 

 

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

 

 

 

Figure 1. Teaching points: AT is distributed throughout the body in various discrete locations, known as depots. These areas of fat deposition are important to consider when studying AT because the composition and secretory profile can vary drastically depending on AT location. For example, while visceral fat pads are often considered "unhealthy" because of their positive correlation with metabolic disease and inflammation, subQ fat does not appear to impart disease risk and is generally regarded as a "healthy" fat pad.

Figure 2. Teaching points: Understanding the differences in AT distribution between humans and mice is important when attempting to translate findings from mouse studies to those performed using human subjects. Human AT distribution shares some common features with that of mice, although there are notable differences. For example, the omental depot in human WAT is much less prominent in mice. Additionally, humans lack the perigonadal fat pad that is commonly used in studies of mouse WAT.

Figure 3. Teaching points: WAT can undergo extensive remodeling in states of obesity. Expansion of WAT occurs in two ways: namely, an increase in cell number (hyperplasia) or cell size (hypertrophy). "Healthy", or normal, fat expansion usually involves an increase in cell number, while "unhealthy", or pathological, expansion often occurs during obesity when there is a shift to increasing cell size. Pathological expansion induces a number of changes within WAT that lead to increased pro-inflammatory immune cell and adipokine response, tissue fibrosis, and hypoxia.

Figure 4. Teaching points: Understanding the regulation of GH secretion is essential for understanding the clinical conditions associated with excess or reduced GH action. Hormones released by the hypothalamus control the secretion of GH, which binds receptors on the liver and stimulates the production of IGF-1. GH exerts its effects both directly and indirectly, via IGF-1, on a number of tissues including fat, muscle, and bone.

Figure 5. Teaching points: The action of GH is mediated through its binding to the GHR. GH-induced intracellular signaling can occur through several pathways.

Figure 6. Teaching points: Genetic alteration of GH action in mice results in many phenotypic changes. Specifically, the effect of GH on body composition is readily observable when comparing these different mouse lines. bGH mice, which have excess GH action, are giant and lean with reduced fat mass. Conversely, GHA and GHR–/– mice have reduced and absent GH action, respectively, resulting in a dwarf phenotype and increased fat mass.

Figure 7. Teaching points: Comparisons of body fat percentage in mice with altered GH action further showcase the negative regulation of fat mass by GH. Initially, bGH mice have greater body fat than WT controls, but have significantly reduced fat mass later in life. In contrast, GHA and GHR-/- mice have greater percentage body fat than WT controls at all-time points.

Figure 8. Teaching points: Picrosirius red staining reveals the effect of GH on collagen deposition in WAT. bGH have increased collagen deposition compared to those with normal or absent GH action.

 

 

 

 

 

 

 

 

 

 


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Katie M. Troike, Brooke E. Henry, Elizabeth A. Jensen, Jonathan A. Young, Edward O. List, John J. Kopchick, Darlene E. Berryman. Impact of Growth Hormone on Regulation of Adipose Tissue. Compr Physiol 2017, 7: 819-840. doi: 10.1002/cphy.c160027