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Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.

Soedling H, Hodson DJ, Adrianssens AE, Gribble FM, Reimann F, Trapp S, Rutter GA - Mol Metab (2015)

Bottom Line: Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2  ±  3.2% decrease in area under curve; p < 0.05), and improved (39.0  ±  13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro.No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio.Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, du Cane Road, London W12 0NN, UK.

ABSTRACT

Aims/hypothesis: The adipose tissue-derived hormone leptin plays an important role in the maintenance of body weight and glucose homeostasis. Leptin mediates its effects by interaction with leptin receptors (LepRb), which are highly expressed in the hypothalamus and other brain centres, and at lower levels in the periphery. Previous studies have used relatively promiscuous or inefficient Cre deleter strains, respectively, to explore the roles of LepR in pancreatic β and α cells. Here, we use two newly-developed Cre lines to explore the role of leptin signalling in insulin and proglucagon-expressing cells.

Methods: Leptin receptor expression was measured in isolated mouse islets and highly-purified islet cells by RNASeq and quantitative RT-PCR. Mice lacking leptin signalling in pancreatic β, or in α and other proglucagon-expressing cells, were generated using Ins1Cre- or iGluCre-mediated recombination respectively of flox'd leptin receptor alleles. In vivo glucose homeostasis, changes in body weight, pancreatic histology and hormone secretion from isolated islets were assessed using standard techniques.

Results: Leptin receptor mRNA levels were at or below the level of detection in wild-type adult mouse isolated islets and purified cells, and leptin signalling to Stat3 phosphorylation was undetectable. Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2  ±  3.2% decrease in area under curve; p < 0.05), and improved (39.0  ±  13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro. No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio. Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro.

Conclusions/interpretation: The use here of a highly selective Cre recombinase indicates that leptin signalling plays a relatively minor, age- and sex-dependent role in the control of β cell function in the mouse. No in vivo role for leptin receptors on α cells, nor in other proglucagon-expressing cells, was detected in this study.

No MeSH data available.


Related in: MedlinePlus

Ins1CreLepRKOfemales display improved glucose tolerance at the age of 8 weeks. (A) Blood glucose concentration following IPGTT in Ins1CreLepRKO (square symbol) and LepRF/F littermate controls (triangles) in 8-week old females: Ins1CreLepRKO, n = 13, LepRF/F, n = 9, (B) 16-week old females: Ins1CreLepRKO, n = 15, LepRF/F, n = 17, (C) 8-weeks old males: Ins1CreLepRKO, n = 8, LepRF/F, n = 7, (D) 16-week old males: Ins1CreLepRKO, n = 13, LepRF/F, n = 10. For all panels, the corresponding body weight and area under curve (AUC) are inset. Data are expressed as the average ± SEM. Statistical analysis was performed using two-way ANOVA *P < 0.05.
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fig3: Ins1CreLepRKOfemales display improved glucose tolerance at the age of 8 weeks. (A) Blood glucose concentration following IPGTT in Ins1CreLepRKO (square symbol) and LepRF/F littermate controls (triangles) in 8-week old females: Ins1CreLepRKO, n = 13, LepRF/F, n = 9, (B) 16-week old females: Ins1CreLepRKO, n = 15, LepRF/F, n = 17, (C) 8-weeks old males: Ins1CreLepRKO, n = 8, LepRF/F, n = 7, (D) 16-week old males: Ins1CreLepRKO, n = 13, LepRF/F, n = 10. For all panels, the corresponding body weight and area under curve (AUC) are inset. Data are expressed as the average ± SEM. Statistical analysis was performed using two-way ANOVA *P < 0.05.

Mentions: To examine in more detail whether disruption of leptin signalling in β cells affected glucose metabolism, animals aged 8, 12 and 16 weeks were subjected to intraperitoneal glucose tolerance tests (IPGTT). At 8 weeks, female Ins1CreLepRKO mice showed transiently improved glucose tolerance, which reversed by 16 weeks (Figure 3A,B). No glycaemic phenotype was identified in male Ins1CreLepRKO at any of the ages examined (Figure 3C,D). Ins1CreLepRKO mice also displayed normal insulin sensitivity (Figure 4A).


Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.

Soedling H, Hodson DJ, Adrianssens AE, Gribble FM, Reimann F, Trapp S, Rutter GA - Mol Metab (2015)

Ins1CreLepRKOfemales display improved glucose tolerance at the age of 8 weeks. (A) Blood glucose concentration following IPGTT in Ins1CreLepRKO (square symbol) and LepRF/F littermate controls (triangles) in 8-week old females: Ins1CreLepRKO, n = 13, LepRF/F, n = 9, (B) 16-week old females: Ins1CreLepRKO, n = 15, LepRF/F, n = 17, (C) 8-weeks old males: Ins1CreLepRKO, n = 8, LepRF/F, n = 7, (D) 16-week old males: Ins1CreLepRKO, n = 13, LepRF/F, n = 10. For all panels, the corresponding body weight and area under curve (AUC) are inset. Data are expressed as the average ± SEM. Statistical analysis was performed using two-way ANOVA *P < 0.05.
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Related In: Results  -  Collection

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fig3: Ins1CreLepRKOfemales display improved glucose tolerance at the age of 8 weeks. (A) Blood glucose concentration following IPGTT in Ins1CreLepRKO (square symbol) and LepRF/F littermate controls (triangles) in 8-week old females: Ins1CreLepRKO, n = 13, LepRF/F, n = 9, (B) 16-week old females: Ins1CreLepRKO, n = 15, LepRF/F, n = 17, (C) 8-weeks old males: Ins1CreLepRKO, n = 8, LepRF/F, n = 7, (D) 16-week old males: Ins1CreLepRKO, n = 13, LepRF/F, n = 10. For all panels, the corresponding body weight and area under curve (AUC) are inset. Data are expressed as the average ± SEM. Statistical analysis was performed using two-way ANOVA *P < 0.05.
Mentions: To examine in more detail whether disruption of leptin signalling in β cells affected glucose metabolism, animals aged 8, 12 and 16 weeks were subjected to intraperitoneal glucose tolerance tests (IPGTT). At 8 weeks, female Ins1CreLepRKO mice showed transiently improved glucose tolerance, which reversed by 16 weeks (Figure 3A,B). No glycaemic phenotype was identified in male Ins1CreLepRKO at any of the ages examined (Figure 3C,D). Ins1CreLepRKO mice also displayed normal insulin sensitivity (Figure 4A).

Bottom Line: Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2  ±  3.2% decrease in area under curve; p < 0.05), and improved (39.0  ±  13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro.No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio.Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, du Cane Road, London W12 0NN, UK.

ABSTRACT

Aims/hypothesis: The adipose tissue-derived hormone leptin plays an important role in the maintenance of body weight and glucose homeostasis. Leptin mediates its effects by interaction with leptin receptors (LepRb), which are highly expressed in the hypothalamus and other brain centres, and at lower levels in the periphery. Previous studies have used relatively promiscuous or inefficient Cre deleter strains, respectively, to explore the roles of LepR in pancreatic β and α cells. Here, we use two newly-developed Cre lines to explore the role of leptin signalling in insulin and proglucagon-expressing cells.

Methods: Leptin receptor expression was measured in isolated mouse islets and highly-purified islet cells by RNASeq and quantitative RT-PCR. Mice lacking leptin signalling in pancreatic β, or in α and other proglucagon-expressing cells, were generated using Ins1Cre- or iGluCre-mediated recombination respectively of flox'd leptin receptor alleles. In vivo glucose homeostasis, changes in body weight, pancreatic histology and hormone secretion from isolated islets were assessed using standard techniques.

Results: Leptin receptor mRNA levels were at or below the level of detection in wild-type adult mouse isolated islets and purified cells, and leptin signalling to Stat3 phosphorylation was undetectable. Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2  ±  3.2% decrease in area under curve; p < 0.05), and improved (39.0  ±  13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro. No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio. Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro.

Conclusions/interpretation: The use here of a highly selective Cre recombinase indicates that leptin signalling plays a relatively minor, age- and sex-dependent role in the control of β cell function in the mouse. No in vivo role for leptin receptors on α cells, nor in other proglucagon-expressing cells, was detected in this study.

No MeSH data available.


Related in: MedlinePlus