Growth hormone controls lipolysis by regulation of FSP27 expression

Sharma, Rita; Luong, Quyen; Sharma, Vishva Mitra; Harberson, Mitchell; Harper, Brian; Colborn, Andrew; Berryman, Darlene E.; Jessen, Niels; Jørgensen, Jens Otto Lunde; Kopchick, John J.; Puri, Vishwajeet; Lee, Kevin Y.

doi:10.1530/joe-18-0282

Cited by 33 publications

(27 citation statements)

References 70 publications

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“…However, we and others have consistently documented the lipolytic effects of GH in vivo by means of more precise measures including glycerol concentrations in serum (Moller, Jorgensen, Alberti, et al, ) as well as in the interstitial fluid by means of microdialysis (Gravholt et al, ), and we have also shown that GH increases fatty acid turnover assessed by tracer techniques (Kanaley et al, ; Krag et al, ; Norrelund et al, ). In recent cell studies, we have also demonstrated that GH acutely stimulates glycerol release (Sharma et al, , ). Second, it is inherently difficult to combine human in vivo studies with animal and in vitro models.…”

Section: Discussionmentioning

confidence: 60%

“…We recently reported that GH downregulates the mRNA and protein expression of fat specific protein 27 (FSP27), also known as CIDEC, in studies involving GH infusion with and without fasting in healthy young male subjects (mean age ≈ 21 years) (Sharma et al, ), as well as in studies in mice(Sharma et al, ) and in human adipocytes in vitro (Sharma et al, ). Fat‐specific protein 27 is an LD‐associated protein that regulates LD dynamics (Jambunathan, Yin, Khan, Tamori, & Puri, ; Puri et al, ) and lipolysis in adipocytes through downregulation of the transcription and activity of ATGL, the rate‐limiting enzyme in lipolysis (Singh et al, ).…”

Section: Discussionmentioning

confidence: 99%

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The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals

et al. 2020

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Aim Since GH stimulates lipolysis in vivo after a 2‐hr lag phase, we studied whether this involves GH signaling and gene expression in adipose tissue (AT). Methods Human subjects (n = 9) each underwent intravenous exposure to GH versus saline with measurement of serum FFA, and GH signaling, gene array, and protein in AT biopsies after 30–120 min. Human data were corroborated in adipose‐specific GH receptor knockout (FaGHRKO) mice versus wild‐type mice. Expression of candidate genes identified in the array were investigated in 3T3‐L1 adipocytes. Results GH increased serum FFA and AT phosphorylation of STAT5b in human subjects. This was replicated in wild‐type mice, but not in FaGHRKO mice. The array identified 53 GH‐regulated genes, and Ingenuity Pathway analysis showed downregulation of PDE3b, an insulin‐dependent antilipolytic signal, upregulation of PTEN that inhibits insulin‐dependent antilipolysis, and downregulation of G0S2 and RASD1, both encoding antilipolytic proteins. This was confirmed in 3T3‐L1 adipocytes, except for PDE3B, including reciprocal effects of GH and insulin on mRNA expression of PTEN, RASD1, and G0S2. Conclusion (a) GH directly stimulates AT lipolysis in a GHR‐dependent manner, (b) this involves suppression of antilipolytic signals at the level of gene expression, (c) the underlying GH signaling pathways remain to be defined.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals

et al. 2020

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“…3T3-L1 adipocytes were grown and differentiated as previously described [32]. 3T3-L1 (from ATCC: CL-173; passages 4–12) were grown in DMEM, high glucose (4.5 g/L), Glutamax, Pen-Strep and 10% FBS and then seeded at 200,000 cells/well in six-well plates for differentiation into adipocytes.…”

Section: Methodsmentioning

confidence: 99%

Temporal patterns of lipolytic regulators in adipose tissue after acute growth hormone exposure in human subjects: A randomized controlled crossover trial

Hjelholt

Lee

Arlien-Søborg³

et al. 2019

Molecular Metabolism

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Objective Growth hormone (GH) stimulates lipolysis, but the underlying mechanisms remain incompletely understood. We examined the effect of GH on the expression of lipolytic regulators in adipose tissue (AT). Methods In a randomized, placebo-controlled, cross-over study, nine men were examined after injection of 1) a GH bolus and 2) a GH-receptor antagonist (pegvisomant) followed by four AT biopsies. In a second study, eight men were examined in a 2 × 2 factorial design including GH infusion and 36-h fasting with AT biopsies obtained during a basal period and a hyperinsulinemic-euglycemic clamp. Expression of GH-signaling intermediates and lipolytic regulators were studied by PCR and western blotting. In addition, mechanistic experiments in mouse models and 3T3-L1 adipocytes were performed. Results The GH bolus increased circulating free fatty acids (p < 0.0001) together with phosphorylation of signal transducer and activator of transcription 5 (STAT5) (p < 0.0001) and mRNA expression of the STAT5-dependent genes cytokine-inducible SH2-containing protein ( CISH ) and IGF-1 in AT. This was accompanied by suppressed mRNA expression of G0/G1 switch gene 2 ( G0S2 ) (p = 0.007) and fat specific protein 27 (FSP27) (p = 0.002) and upregulation of phosphatase and tensin homolog ( PTEN ) mRNA expression (p = 0.03). Suppression of G0S2 was also observed in humans after GH infusion and fasting, as well as in GH transgene mice, and in vitro studies suggested MEK-PPARγ signaling to be involved. Conclusions GH-induced lipolysis in human subjects in vivo is linked to downregulation of G0S2 and FSP27 and upregulation of PTEN in AT. Mechanistically, in vitro data suggest that GH acts via MEK to suppress PPARγ-dependent transcription of G0S2 . ClinicalTrials.gov NCT02782221 and NCT01209429 .

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“…STAT5 mediates the GH-effects on lipolysis by increasing the transcription of several metabolic genes such as peroxisome proliferator-activated receptor (PPAR)-gamma and fatty acid synthase (73, 74). In addition, both STAT5- and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent intracellular signaling mediate the effects on GH in suppressing mRNA and protein levels of fat-specific protein 27 (FSP27), a negative regulator of lipolysis (75). The importance of FSP27 supression for GH signaling in adipocytes is highlighted by the fact that FSP27 overexpression fully abrogates the effects of GH on lipolysis and insulin resistance in adipose tissue, mainly by inhibiting PPAR-gamma phosphorylation (75, 76).…”

Section: Pathophysiology Of Insulin Resistance In Acromegalymentioning

confidence: 99%

Insulin Resistance in Patients With Acromegaly

et al. 2019

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Acromegaly is characterized by chronic overproduction of growth hormone (GH) that leads to insulin resistance, glucose intolerance and, ultimately, diabetes. The GH-induced sustained stimulation of lipolysis plays a major role not only in the development of insulin resistance and prediabetes/diabetes, but also in the reduction of lipid accumulation, making acromegaly a unique case of severe insulin resistance in the presence of reduced body fat. In the present review, we elucidate the effects of GH hypersecretion on metabolic organs, describing the pathophysiology of impaired glucose tolerance in acromegaly, as well as the impact of acromegaly-specific therapies on glucose metabolism. In addition, we highlight the role of insulin resistance in the development of acromegaly-associated complications such as hypertension, cardiac disease, sleep apnea, polycystic ovaries, bone disease, and cancer. Taken together, insulin resistance is an important metabolic hallmark of acromegaly, which is strongly related to disease activity, the development of comorbidities, and might even impact the response to drugs used in the treatment of acromegaly.

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Growth hormone controls lipolysis by regulation of FSP27 expression

Cited by 33 publications

References 70 publications

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals

Temporal patterns of lipolytic regulators in adipose tissue after acute growth hormone exposure in human subjects: A randomized controlled crossover trial

Insulin Resistance in Patients With Acromegaly

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