Growth hormone controls lipolysis by regulation of FSP27 expression

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

Download Full-text

Growth hormone acts along the PPARγ-FSP27 axis to stimulate lipolysis in human adipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00129.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. E34-E42 ◽

Cited By ~ 12

Author(s):

Vishva M. Sharma ◽

Esben Thyssen Vestergaard ◽

Niels Jessen ◽

Peter Kolind-Thomsen ◽

Birgitte Nellemann ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Physiological Role ◽

Negative Regulator ◽

Peroxisome Proliferator ◽

Human Adipocytes ◽

Gh Treatment ◽

Signaling Mechanism

The lipolytic effects of growth hormone (GH) have been known for half a century and play an important physiological role for substrate metabolism during fasting. In addition, sustained GH-induced lipolysis is causally linked to insulin resistance. However, the underlying molecular mechanisms remain elusive. In the present study, we obtained experimental data in human subjects and used human adipose-derived stromal vascular cells (hADSCs) as a model system to elucidate GH-triggered molecular signaling that stimulates adipose tissue lipolysis and insulin resistance in human adipocytes. We discovered that GH downregulates the expression of fat-specific protein (FSP27), a negative regulator of lipolysis, by impairing the transcriptional ability of the master transcriptional regulator, peroxisome proliferator-activated receptor-γ (PPARγ) via MEK/ERK activation. Ultimately, GH treatment promotes phosphorylation of PPARγ at Ser273 and causes its translocation from nucleus to the cytosol. Surprisingly, FSP27 overexpression inhibited PPARγ Ser273 phosphorylation and promoted its nuclear retention. GH antagonist treatment had similar effects. Our study identifies a novel signaling mechanism by which GH transcriptionally induces lipolysis via the MEK/ERK pathway that acts along PPARγ-FSP27 in human adipose tissue.

Download Full-text

Modulation of insulin signalling by insulin sensitizers

Biochemical Society Transactions ◽

10.1042/bst0330358 ◽

2005 ◽

Vol 33 (2) ◽

pp. 358-361 ◽

Cited By ~ 15

Author(s):

G. Jiang ◽

B.B. Zhang

Keyword(s):

Insulin Resistance ◽

Molecular Mechanisms ◽

Insulin Signalling ◽

Serine Phosphorylation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Hek 293 ◽

Insulin Sensitizers ◽

Obese Rats

Insulin resistance is a hallmark of Type II diabetes. It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor γ agonists and aspirin improve insulin action in vivo. The detailed mechanisms by which the insulin sensitizers promote insulin signalling, however, are not completely understood and remain somewhat controversial. In the present review, we summarize our studies attempting to explore the molecular mechanisms underlying the effects of insulin sensitizers in cells and in animal models of insulin resistance. In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor γ agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. Treatment of the Zucker obese rats with rosiglitazone for 24 h also reversed the high circulating levels of free fatty acids, which have been shown to correlate with increased IRS1 serine phosphorylation. Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo.

Download Full-text

Opposing Roles of Peroxisome Proliferator-activated Receptor α and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model

Journal of Biological Chemistry ◽

10.1074/jbc.m902074200 ◽

2009 ◽

Vol 284 (24) ◽

pp. 16541-16552 ◽

Cited By ~ 23

Author(s):

Üzen Savas ◽

Daniel E. W. Machemer ◽

Mei-Hui Hsu ◽

Pryce Gaynor ◽

Jerome M. Lasker ◽

...

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Transgenic Mice ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Peroxisome Proliferator ◽

Sexually Dimorphic ◽

Peroxisome Proliferator Activated Receptor ◽

Liver And Kidney

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for ω-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2–3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor α (PPARα) null mice. Dietary administration of either of the PPARα agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2–3-fold, and these responses were also abrogated in PPARα null mice. Basal liver CYP4A11 levels are reduced differentially in PPARα−/− females (>95%) and males (<50%) compared with PPARα−/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARα-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARα−/− CYP4A11 Tg male mice to levels similar to that of female PPARα-deficient mice. These results suggest that PPARα contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.

Download Full-text

Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m608172200 ◽

2006 ◽

Vol 282 (7) ◽

pp. 4417-4426 ◽

Cited By ~ 32

Author(s):

Cicerone Tudor ◽

Jérôme N. Feige ◽

Harikishore Pingali ◽

Vidya Bhushan Lohray ◽

Walter Wahli ◽

...

Keyword(s):

Ligand Binding ◽

Molecular Mechanisms ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Living Cells ◽

Correlation Spectroscopy ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Peroxisome Proliferator Activated Receptors

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Download Full-text

Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1

Scientific Reports ◽

10.1038/s41598-020-76564-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Nandini Ghosh ◽

Amitava Das ◽

Nirupam Biswas ◽

Surya Gnyawali ◽

Kanhaiya Singh ◽

...

Keyword(s):

Skeletal Muscle ◽

Molecular Mechanisms ◽

C2c12 Cells ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Urolithin A ◽

Silent Information Regulator 1 ◽

Angiogenic Markers ◽

Pathway Inhibition

AbstractUrolithin A (UA) is a natural compound that is known to improve muscle function. In this work we sought to evaluate the effect of UA on muscle angiogenesis and identify the underlying molecular mechanisms. C57BL/6 mice were administered with UA (10 mg/body weight) for 12–16 weeks. ATP levels and NAD+ levels were measured using in vivo 31P NMR and HPLC, respectively. UA significantly increased ATP and NAD+ levels in mice skeletal muscle. Unbiased transcriptomics analysis followed by Ingenuity Pathway Analysis (IPA) revealed upregulation of angiogenic pathways upon UA supplementation in murine muscle. The expression of the differentially regulated genes were validated using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Angiogenic markers such as VEGFA and CDH5 which were blunted in skeletal muscles of 28 week old mice were found to be upregulated upon UA supplementation. Such augmentation of skeletal muscle vascularization was found to be bolstered via Silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α) pathway. Inhibition of SIRT1 by selisistat EX527 blunted UA-induced angiogenic markers in C2C12 cells. Thus this work provides maiden evidence demonstrating that UA supplementation bolsters skeletal muscle ATP and NAD+ levels causing upregulated angiogenic pathways via a SIRT1-PGC-1α pathway.

Download Full-text

Musclin is an activity-stimulated myokine that enhances physical endurance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1514250112 ◽

2015 ◽

Vol 112 (52) ◽

pp. 16042-16047 ◽

Cited By ~ 58

Author(s):

Ekaterina Subbotina ◽

Ana Sierra ◽

Zhiyong Zhu ◽

Zhan Gao ◽

Siva Rama Krishna Koganti ◽

...

Keyword(s):

Exercise Capacity ◽

Exercise Tolerance ◽

Skeletal Muscles ◽

Molecular Mechanisms ◽

Mitochondrial Protein ◽

Guanosine Monophosphate ◽

Physical Endurance ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Exercise remains the most effective way to promote physical and metabolic wellbeing, but molecular mechanisms underlying exercise tolerance and its plasticity are only partially understood. In this study we identify musclin—a peptide with high homology to natriuretic peptides (NP)—as an exercise-responsive myokine that acts to enhance exercise capacity in mice. We use human primary myoblast culture and in vivo murine models to establish that the activity-related production of musclin is driven by Ca2+-dependent activation of Akt1 and the release of musclin-encoding gene (Ostn) transcription from forkhead box O1 transcription factor inhibition. Disruption of Ostn and elimination of musclin secretion in mice results in reduced exercise tolerance that can be rescued by treatment with recombinant musclin. Reduced exercise capacity in mice with disrupted musclin signaling is associated with a trend toward lower levels of plasma atrial NP (ANP) and significantly smaller levels of cyclic guanosine monophosphate (cGMP) and peroxisome proliferator-activated receptor gamma coactivator 1-α in skeletal muscles after exposure to exercise. Furthermore, in agreement with the established musclin ability to interact with NP clearance receptors, but not with NP guanyl cyclase-coupled signaling receptors, we demonstrate that musclin enhances cGMP production in cultured myoblasts only when applied together with ANP. Elimination of the activity-related musclin-dependent boost of ANP/cGMP signaling results in significantly lower maximum aerobic capacity, mitochondrial protein content, respiratory complex protein expression, and succinate dehydrogenase activity in skeletal muscles. Together, these data indicate that musclin enhances physical endurance by promoting mitochondrial biogenesis.

Download Full-text

Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00126.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. E536-E543 ◽

Cited By ~ 21

Author(s):

Chaodong Wu ◽

Salmaan A. Khan ◽

Li-Jen Peng ◽

Honggui Li ◽

Steven G. Carmella ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Flux ◽

Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

Download Full-text

Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

Endocrinology ◽

10.1210/en.2015-1322 ◽

2015 ◽

Vol 156 (10) ◽

pp. 3610-3624 ◽

Cited By ~ 68

Author(s):

Gabriele Schoiswohl ◽

Maja Stefanovic-Racic ◽

Marie N. Menke ◽

Rachel C. Wills ◽

Beth A. Surlow ◽

...

Keyword(s):

Insulin Resistance ◽

Target Genes ◽

Immune Cell ◽

Cell Infiltration ◽

Peroxisome Proliferator ◽

Immune Cell Infiltration ◽

Lipid Uptake ◽

Peroxisome Proliferator Activated Receptor ◽

Triacylglycerol Hydrolysis

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

Download Full-text

The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies

Cancers ◽

10.3390/cancers12092623 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2623

Author(s):

Giuseppina Augimeri ◽

Cinzia Giordano ◽

Luca Gelsomino ◽

Pierluigi Plastina ◽

Ines Barone ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Studies ◽

Molecular Mechanisms ◽

Basic Research ◽

Therapeutic Effects ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Natural And Synthetic

Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.

Download Full-text