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Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance.

Huynh FK, Levi J, Denroche HC, Gray SL, Voshol PJ, Neumann UH, Speck M, Chua SC, Covey SD, Kieffer TJ - Diabetes (2010)

Bottom Line: Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body.Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body.Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT

Objective: The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.

Research design and methods: To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.

Results: The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.

Conclusions: These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

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Related in: MedlinePlus

Leprflox/flox Albcre tg+ mice have a liver-specific loss of the leptin receptor signaling domain. A: Genomic DNA from tissues of Leprflox/flox mice with and without the Albcre transgene was used as template for PCR of the Leprflox allele. The predicted product sizes are 1,369 bp for Leprflox and 952 bp for LeprΔ17. B: RNA was extracted from the livers of Leprflox/flox mice and used as template for RT-PCR with primers flanking exon 17. The predicted product sizes are 343 bp for Leprflox and 267 bp for LeprΔ17 transcripts. Arrows to the left mark the migration of molecular weight markers in bp.
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Figure 1: Leprflox/flox Albcre tg+ mice have a liver-specific loss of the leptin receptor signaling domain. A: Genomic DNA from tissues of Leprflox/flox mice with and without the Albcre transgene was used as template for PCR of the Leprflox allele. The predicted product sizes are 1,369 bp for Leprflox and 952 bp for LeprΔ17. B: RNA was extracted from the livers of Leprflox/flox mice and used as template for RT-PCR with primers flanking exon 17. The predicted product sizes are 343 bp for Leprflox and 267 bp for LeprΔ17 transcripts. Arrows to the left mark the migration of molecular weight markers in bp.

Mentions: Following generation of Leprflox/flox Albcre tg+ and Leprflox/flox Albcre tg− littermate controls, we investigated the extent and specificity of Cre-mediated excision of exon 17 of the leptin receptor. In all tissues tested, there was a PCR product of ∼1,370 bp, which corresponds to the expected product size of the Leprflox allele (Fig. 1A). Although present, there was very little of this amplicon generated from liver DNA of Leprflox/flox Albcre tg+ mice, likely contributed by non-hepatocytes. Instead, the major product amplified from liver DNA of Leprflox/flox Albcre tg+ mice was ∼950 bp in size, which corresponds to the expected size of the Leprflox allele following Cre-mediated excision (resulting in LeprΔ17). Thus, it appears that in the Leprflox/flox Albcre tg+ mice, excision at the Leprflox allele among the tissues tested was restricted to the liver and that the majority of hepatocytes carry the LeprΔ17 rather than the Leprflox allele. Consistent with this, an analysis of Lepr-b mRNA transcripts by RT-PCR revealed that while the only amplified product detected from the liver of Leprflox/flox Albcre tg− mice corresponded to the anticipated 343 bp product from the wild-type Lepr-b transcript, in the liver of the Leprflox/flox Albcre tg+ mice, only an amplicon of the predicted size of the LeprΔ17 transcript was detected (Fig. 1B). The LeprΔ17 transcript has been previously shown to result in impaired leptin-stimulated JAK/STAT signaling in mouse lines derived from the same Leprflox/flox mice used in our study (24,28). Thus, our mice, which we have shown to predominantly express the LeprΔ17 allele specifically in the liver, must have impaired leptin-stimulated hepatic JAK/STAT activation.


Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance.

Huynh FK, Levi J, Denroche HC, Gray SL, Voshol PJ, Neumann UH, Speck M, Chua SC, Covey SD, Kieffer TJ - Diabetes (2010)

Leprflox/flox Albcre tg+ mice have a liver-specific loss of the leptin receptor signaling domain. A: Genomic DNA from tissues of Leprflox/flox mice with and without the Albcre transgene was used as template for PCR of the Leprflox allele. The predicted product sizes are 1,369 bp for Leprflox and 952 bp for LeprΔ17. B: RNA was extracted from the livers of Leprflox/flox mice and used as template for RT-PCR with primers flanking exon 17. The predicted product sizes are 343 bp for Leprflox and 267 bp for LeprΔ17 transcripts. Arrows to the left mark the migration of molecular weight markers in bp.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992763&req=5

Figure 1: Leprflox/flox Albcre tg+ mice have a liver-specific loss of the leptin receptor signaling domain. A: Genomic DNA from tissues of Leprflox/flox mice with and without the Albcre transgene was used as template for PCR of the Leprflox allele. The predicted product sizes are 1,369 bp for Leprflox and 952 bp for LeprΔ17. B: RNA was extracted from the livers of Leprflox/flox mice and used as template for RT-PCR with primers flanking exon 17. The predicted product sizes are 343 bp for Leprflox and 267 bp for LeprΔ17 transcripts. Arrows to the left mark the migration of molecular weight markers in bp.
Mentions: Following generation of Leprflox/flox Albcre tg+ and Leprflox/flox Albcre tg− littermate controls, we investigated the extent and specificity of Cre-mediated excision of exon 17 of the leptin receptor. In all tissues tested, there was a PCR product of ∼1,370 bp, which corresponds to the expected product size of the Leprflox allele (Fig. 1A). Although present, there was very little of this amplicon generated from liver DNA of Leprflox/flox Albcre tg+ mice, likely contributed by non-hepatocytes. Instead, the major product amplified from liver DNA of Leprflox/flox Albcre tg+ mice was ∼950 bp in size, which corresponds to the expected size of the Leprflox allele following Cre-mediated excision (resulting in LeprΔ17). Thus, it appears that in the Leprflox/flox Albcre tg+ mice, excision at the Leprflox allele among the tissues tested was restricted to the liver and that the majority of hepatocytes carry the LeprΔ17 rather than the Leprflox allele. Consistent with this, an analysis of Lepr-b mRNA transcripts by RT-PCR revealed that while the only amplified product detected from the liver of Leprflox/flox Albcre tg− mice corresponded to the anticipated 343 bp product from the wild-type Lepr-b transcript, in the liver of the Leprflox/flox Albcre tg+ mice, only an amplicon of the predicted size of the LeprΔ17 transcript was detected (Fig. 1B). The LeprΔ17 transcript has been previously shown to result in impaired leptin-stimulated JAK/STAT signaling in mouse lines derived from the same Leprflox/flox mice used in our study (24,28). Thus, our mice, which we have shown to predominantly express the LeprΔ17 allele specifically in the liver, must have impaired leptin-stimulated hepatic JAK/STAT activation.

Bottom Line: Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body.Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body.Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT

Objective: The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.

Research design and methods: To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.

Results: The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.

Conclusions: These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

Show MeSH
Related in: MedlinePlus