Weight cycling impairs pancreatic insulin secretion but does not perturb whole-body insulin action in diet-induced obese mice
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ABSTRACT:
PROVIDER: PRJNA837063 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19164963_1.fastq.gz | Fastqsanger.gz | |||
| SRR19164963_2.fastq.gz | Fastqsanger.gz | |||
| SRR19164964_1.fastq.gz | Fastqsanger.gz | |||
| SRR19164964_2.fastq.gz | Fastqsanger.gz | |||
| SRR19164965_1.fastq.gz | Fastqsanger.gz |
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Project description:In the setting of obesity and insulin resistance, glycemia is controlled in part by beta cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of drivers of b-cell identity (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared to those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.
2022-11-09 | GSE202697 | GEO
Project description:Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, has been shown to deliver enhanced glycemic control and superior weight loss compared to a selective GLP-1 receptor (GLP-1R) agonist in patients with type 2 diabetes mellitus. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes to the therapy is not fully understood. Here, hyperinsulinemic-euglycemic clamp studies were used to show that tirzepatide is a highly effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes to the insulin sensitization, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R induced weight loss, tirzepatide improved systemic insulin sensitivity by enhancing glucose disposal in WAT. To corroborate these results, chronic treatment with a long-acting GIPR agonist (LAGIPRA) was also found to enhance insulin sensitivity by increasing insulin stimulated glucose uptake in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched chain amino and keto acids in the circulation. Whole-body insulin sensitization was associated with pronounced upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual GIP and GLP-1 receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
2021-04-29 | GSE173522 | GEO
Project description:Chronic GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese insulin resistant mice
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Project description:Background. Differential gene expression in adipose tissue during diet-induced weight loss followed by a weight stability period is not well characterized. Markers of these processes may provide a deeper understanding of the underlying mechanisms. Objective. To identify differentially expressed genes in human adipose tissue during weight loss and weight maintenance after weight loss. Design. RNA from subcutaneous abdominal adipose tissue from nine obese subjects was obtained and analyzed at baseline, after weight reduction on a low calorie diet (LCD), and after a period of group therapy in order to maintain weight stability. Results. Subjects lost 18.8 + 5.4% of their body weight during the LCD and maintained this weight during group therapy. Insulin sensitivity (HOMA) improved after weight loss with no further improvement during weight maintenance. Cyclin-dependent kinase inhibitor 2B (CDKN2B) and JAZF zinc finger 1 (JAZF1), associated with type 2 diabetes, were downregulated. We could also confirm the downregulation of candidates for obesity and related traits, such as tenomodulin (TNMD) and matrix metallopeptidase 9 (MMP9), with weight loss. The expression of other candidates, such as cell death-inducing DFFA-like effector A (CIDEA) and stearoyl-CoA desaturase (SCD) were upregulated during weight loss but returned to baseline levels during weight maintenance. Conclusion. Genes in the adipose tissue are differentially expressed during weight loss and weight maintenance after weight loss. Genes that show sustained regulation may be of potential interest as markers of the beneficial effects of weight loss whereas others seem to be primarily involved in the process of weight loss itself.
2012-01-31 | GSE35411 | GEO
Project description:The purpose of this study was to conduct a randomized-controlled trial to evaluate the effect of a high-protein (HP) diet weight loss (WL) on changes in body composition, insulin sensitivity and skeletal muscle gene expression profile in postmenopausal women who were obese and randomized to one of three dietary intervention groups: 1) a weight maitenance group, 2) a weight loss group (normal protein intake, 0.8 g protein/kg body weight per day) and 3) a weight loss group (high protein intake, 1.2 g protein/kg body weight per day) and studies before and after they lost 10% of their body weight (WL groups) or a time-matched weight maintenacne period.
2016-12-01 | GSE73525 | GEO
Project description:Background. Differential gene expression in adipose tissue during diet-induced weight loss followed by a weight stability period is not well characterized. Markers of these processes may provide a deeper understanding of the underlying mechanisms. Objective. To identify differentially expressed genes in human adipose tissue during weight loss and weight maintenance after weight loss. Design. RNA from subcutaneous abdominal adipose tissue from nine obese subjects was obtained and analyzed at baseline, after weight reduction on a low calorie diet (LCD), and after a period of group therapy in order to maintain weight stability. Results. Subjects lost 18.8 + 5.4% of their body weight during the LCD and maintained this weight during group therapy. Insulin sensitivity (HOMA) improved after weight loss with no further improvement during weight maintenance. Cyclin-dependent kinase inhibitor 2B (CDKN2B) and JAZF zinc finger 1 (JAZF1), associated with type 2 diabetes, were downregulated. We could also confirm the downregulation of candidates for obesity and related traits, such as tenomodulin (TNMD) and matrix metallopeptidase 9 (MMP9), with weight loss. The expression of other candidates, such as cell death-inducing DFFA-like effector A (CIDEA) and stearoyl-CoA desaturase (SCD) were upregulated during weight loss but returned to baseline levels during weight maintenance. Conclusion. Genes in the adipose tissue are differentially expressed during weight loss and weight maintenance after weight loss. Genes that show sustained regulation may be of potential interest as markers of the beneficial effects of weight loss whereas others seem to be primarily involved in the process of weight loss itself. Nine participants were prescribed a low calorie diet (LCD) containing 1200 kcal/day for approximately three months (101 ± 26 days). Following the weight reduction phase the participants attended a six month follow-up period (167 ± 37 days). By protocol design, subjects were eligible to enter the study if they had lost at least 10% of their initial body weight during the LCD-period and maintained this weight (+5%) after group therapy. Subcutaneous adipose tissue samples were obtained at three time-points: (i) at baseline, (ii) after weight reduction when subjects were no longer losing weight, and (iii) after the group therapy weight maintenance phase.
2012-01-31 | E-GEOD-35411 | biostudies-arrayexpress
Project description:Illumina paired-end sequencing of whole- exome pulldown DNA from Severe Insulin Resistant patients.
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Project description:Insulin secreted by pancreatic β cells is essential for maintaining the level of blood glucose. Diabetes is mainly caused by the loss of β cells or impaired β cell function. The previous study performed a whole transcriptome analysis on the islets of T2D and the control group, and the results showed that the splicing disorder of the splicing event was about 25%, breast carcinoma amplified sequence 2(BCAS2) is one of the components of the spliceosome, and its function in islet β cell is unclear. Here we report that knockdown of Bcas2 decreases in glucose and KCl-stimulated insulin secretion in the NIT-1 cell line. The pancreas weight, glucose tolerance and insulin sensitivity were detected in normal chow-fed and high-fat diet-fed Bcas2 f/f-βKO mice, and β cell mass and islet size was analyzed by immunohistochemistry. Glucose intolerance developed in Bcas2 f/f-βKO mice, but there were no significant differences in pancreas weight, insulin sensitivity, β cell mass and islet size. Further, GSIS and observation of insulin secretion granules were performed on normal chow-fed mice, and it was found that the insulin level in serum decreased and the number of insulin secretion granules decreased in Bcas2 f/f-βKO mice, which was related to the abnormal splicing of Syt7 and Tcf7l2 pre-mRNA. Taken together, these results demonstrate that BCAS2 is involved in alternative splicing during insulin synthesis and secretion. Elisa,islet isolation,insulin secretion
2024-06-01 | GSE224490 | GEO
Project description:Gene expression change on weight cycling mice eWAT
2018-06-07 | GSE73345 | GEO
Project description:The activity of pancreatic islets’ insulin-producing β-cells is closely regulated by systemic cues and, locally, by adjacent islet hormone-producing “non-β-cells” (namely α-, δ- and γ-cells). Still, it is unclear whether the presence of the non-β-cells is a requirement for accurate insulin secretion. Here, we generated and studied a mouse model in which adult islets are exclusively composed of β-cells, and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation. They exhibited enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was like in intact islets, both in homeostatic conditions and upon extreme insulin demand. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of human islets comprising all four cell types. Together, the findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. This is particularly relevant in diabetes, where non-β-cells become dysfunctional and worsen the disease’s pathophysiology. These results support efforts aimed at developing diabetes treatments by generating β-like cell clusters devoid of non-β-cells, as for example from human embryonic stem cells and/or by in situ conversion of non-β-cells into insulin producers.
2024-07-19 | GSE226479 | GEO