Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis

Richard, Allison J.; Hang, Hardy; Zhao, Peng; Mendoza, Tamra; Ghosh, Sujoy; Elks, Carrie M.; Stephens, Jacqueline M.

doi:10.3389/fendo.2022.812802

Cited by 8 publications

(6 citation statements)

References 68 publications

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“…Because Lama4 is expressed in blood vessels and immune cells, we did not expect to observe a complete loss of Lama4 in adipose tissue. The results we observed, in this case, are consistent with those from whole fat tissue of other adipocyte-specific models we have generated [ 14 , 17 ]. Using control ( Lama4 fl/fl ) and Lama4 AKO mice under normal diet conditions, we noted no significant differences in total body mass ( Figure 3 b), fat mass, or lean mass ( Figure 3 c) between genotypes.…”

Section: Resultssupporting

confidence: 91%

“…RNA was isolated from eWAT as described previously [ 14 , 16 , 17 ]. RNA quality was confirmed using a Bioanalyzer RNA 6000 chip (Agilent Technologies, Santa Clara, CA, USA); RNA integrity numbers were verified for all samples and ranged from 8–10.…”

Section: Methodsmentioning

confidence: 99%

“…RNA quality was confirmed using a Bioanalyzer RNA 6000 chip (Agilent Technologies, Santa Clara, CA, USA); RNA integrity numbers were verified for all samples and ranged from 8–10. Sequencing libraries were constructed, library sizes verified, and sequencing conducted as previously described [ 17 ]. Primary data analysis was performed using the Lexogen QuantSeq pipeline V1.8.8 (Lexogen, Inc., Greenland, NH, USA) on the Bluebee platform for quality control, mapping, and read count tables.…”

Section: Methodsmentioning

confidence: 99%

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Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

et al. 2022

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Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in vascular defects that complicate the interpretation of metabolic data. Here, we describe the generation and initial phenotypic analysis of an adipocyte-specific LAMA4 knockout mouse (Lama4AKO). We first performed an in-silico analysis to determine the degree to which laminin α4 was expressed in human and murine adipocytes. Next, male Lama4AKO and control mice were fed chow or high-fat diets and glucose tolerance was assessed along with serum insulin and leptin levels. Adipocyte area was measured in both epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively), and eWAT was used for RNA-sequencing. We found that laminin α4 was highly expressed in human and murine adipocytes. Further, chow-fed Lama4AKO mice are like control mice in terms of body weight, body composition, and glucose tolerance, although they have larger eWAT adipocytes and lower insulin levels. High-fat-fed Lama4AKO mice are fatter and more glucose tolerant when compared to control mice. Transcriptionally, the eWAT of high-fat fed Lama4AKO mice resembles that of chow-fed control mice. We conclude from these findings that adipocyte-specific LAMA4 deletion is protective in an obesogenic environment, even though overall adiposity is increased.

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Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

et al. 2022

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“…However, there have been studies showing that GH directly stimulated lipolysis ( 15 , 40 – 43 ), perhaps through the GH receptor-mediated JAK2-STAT5 pathway ( 44 , 45 ) or the MEK-ERK pathway ( 8 ). Adding to these conflicting results is a recent study finding that adipocyte-specific STAT5 knockout did not affect lipolysis in subcutaneous or inguinal adipose tissue in mice ( 46 ). These discrepancies are difficult to reconcile.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone stimulates lipolysis in mice but not in adipose tissue or adipocyte culture

Zhao

Jiang

2023

Front. Endocrinol.

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The inhibitory effect of growth hormone (GH) on adipose tissue growth and the stimulatory effect of GH on lipolysis are well known, but the mechanisms underlying these effects are not completely understood. In this study, we revisited the effects of GH on adipose tissue growth and lipolysis in the lit/lit mouse model. The lit/lit mice are GH deficient because of a mutation in the GH releasing hormone receptor gene. We found that the lit/lit mice had more subcutaneous fat and larger adipocytes than their heterozygous lit/+ littermates and that these differences were partially reversed by 4-week GH injection. We also found that GH injection to the lit/lit mice caused the mature adipose tissue and adipocytes to reduce in size. These results demonstrate that GH inhibits adipose tissue growth at least in part by stimulating lipolysis. To determine the mechanism by which GH stimulates lipolysis, we cultured adipose tissue explants and adipocytes derived from lit/lit mice with GH and/or isoproterenol, an agonist of the beta-adrenergic receptors. These experiments showed that whereas isoproterenol, expectedly, stimulated potent lipolysis, GH, surprisingly, had no effect on basal lipolysis or isoproterenol-induced lipolysis in adipose tissue explants or adipocytes. We also found that both isoproterenol-induced lipolysis and phosphorylation of hormone-sensitive lipase were not different between lit/lit and lit/+ mice. Taken together, these results support the conclusion that GH has lipolytic effect in mice but argue against the notion that GH stimulates lipolysis by directly acting on adipocytes or by enhancing β-adrenergic receptors-mediated lipolysis.

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“…In obese people, however, insulin’s suppressive effect on lipolysis is diminished [ 18 ]. Insulin resistance in adipose tissue causes extra FFA to be released into circulation, resulting in increased diacylglycerol (DAG) and triacylglycerol (TAG) production in muscle cells and hepatocytes, culminating in ectopic fat deposition [ 19 ]. Consequently, DAG can activate protein kinase C (PKC) in muscle and liver [ 20 ], inhibiting insulin signaling and promoting skeletal muscle and liver insulin resistance, leading to systemic insulin resistance [ 21 ] and a variety of metabolic disorders such as hyperglycemia, hypertension, dyslipidemia, non-alcoholic fatty liver (NAFLD) and T2D [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Analysis from Normal Glucose Tolerance to T2D of Obese Individuals Using Bioinformatic Tools

Errafii

Boujraf

Chikri

2023

IJMS

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Understanding the role of white adipose tissue (WAT) in the occurrence and progression of metabolic syndrome is of considerable interest; among the metabolic syndromes are obesity and type 2 diabetes (T2D). Insulin resistance is a key factor in the development of T2D. When the target cells become resistant to insulin, the pancreas responds by producing more insulin to try to lower blood glucose. Over time, this can lead to a state of hyperinsulinemia (high levels of insulin in the blood), which can further exacerbate insulin resistance and contribute to the development of T2D. In order to understand the difference between healthy and unhealthy obese individuals, we have used published transcriptomic profiling to compare differences between the WAT obtained from obese diabetics and subjects who are obese with normal glucose tolerance and insulin resistance. The identification of aberrantly expressed messenger RNA (mRNA) and the resulting molecular interactions and signaling networks is essential for a better understanding of the progression from normal glucose-tolerant obese individuals to obese diabetics. Computational analyses using Ingenuity Pathway Analysis (IPA) identified multiple activated signaling networks in obesity progression from insulin-resistant and normal glucose-tolerant (IR-NGT) individuals to those with T2D. The pathways affected are: Tumor Necrosis Factor (TNF), Extracellular signal-Regulated protein Kinase 1/2 ERK1/2, Interleukin 1 A (IL1A), Protein kinase C (Pkcs), Convertase C5, Vascular endothelial growth factor (Vegf), REL-associated protein (RELA), Interleukin1/1 B (IL1/1B), Triggering receptor expressed on myeloid cells (TREM1) and Nuclear factor KB1 (NFKB1) networks, while functional annotation highlighted Liver X Receptor (LXR) activation, phagosome formation, tumor microenvironment pathway, LPS/IL-1 mediated inhibition of RXR function, TREM1 signaling and IL-6 signaling. Together, by conducting a thorough bioinformatics study of protein-coding RNAs, prospective targets could be exploited to clarify the molecular pathways underlying the development of obesity-related type 2 diabetes.

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Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis

Cited by 8 publications

References 68 publications

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

Growth hormone stimulates lipolysis in mice but not in adipose tissue or adipocyte culture

Transcriptomic Analysis from Normal Glucose Tolerance to T2D of Obese Individuals Using Bioinformatic Tools

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