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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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Attenuation of hepatic leptin signaling results in increased insulin-stimulated phosphorylation of Akt in the liver. Following the hyperinsulinemic-euglycemic clamp, liver tissues were harvested and flash-frozen. Liver lysates were prepared and Western blots performed for phosphorylated and total Akt levels. Representative blots from two Leprflox/flox Albcre tg− and two Leprflox/flox Albcre tg+ mice are shown in A. Quantification of all samples by densitometry is shown in B, n ≥ 8. Data are mean ± SEM. p-Akt, phosphorylated Akt.
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Figure 7: Attenuation of hepatic leptin signaling results in increased insulin-stimulated phosphorylation of Akt in the liver. Following the hyperinsulinemic-euglycemic clamp, liver tissues were harvested and flash-frozen. Liver lysates were prepared and Western blots performed for phosphorylated and total Akt levels. Representative blots from two Leprflox/flox Albcre tg− and two Leprflox/flox Albcre tg+ mice are shown in A. Quantification of all samples by densitometry is shown in B, n ≥ 8. Data are mean ± SEM. p-Akt, phosphorylated Akt.

Mentions: To more specifically explore insulin sensitivity at the level of the liver in male mice, hyperinsulinemic-euglycemic clamp studies were performed. Figure 6A and B shows that hyperinsulinemia was achieved while maintaining euglycemia during the clamp, and that no differences in blood glucose or plasma insulin levels were observed between Leprflox/flox Albcre tg+ and their Leprflox/flox Albcre tg− littermate controls. In the basal (non-hyperinsulinemic) state, whole-body glucose utilization and endogenous glucose production were similar for the Leprflox/flox Albcre tg+ and Leprflox/flox Albcre tg− littermate controls (Fig. 6C). As expected, in both Leprflox/flox Albcre tg+ and Leprflox/flox Albcre tg− mice, glucose utilization increased and endogenous glucose production decreased in the hyperinsulinemic phase. While whole-body glucose utilization was similar between the mice with and without hepatic leptin signaling, there was a significant difference in insulin-induced suppression of endogenous glucose production (P = 0.03). In the littermate controls, insulin suppressed glucose production by 39%, while in the Leprflox/flox Albcre tg+ mice, insulin suppressed glucose production by 68%. Since the majority of endogenously produced glucose comes from hepatocytes, these data provide evidence that a loss of hepatic leptin signaling mediates enhanced insulin sensitivity in the liver. This notion is supported by our finding that levels of phosphorylated Akt, a key mediator of insulin signaling, was increased in mice lacking hepatic leptin signaling when compared with littermate controls (Fig. 7). Taken together, our data suggest that a loss of hepatic leptin signaling leads to increased insulin sensitivity in the liver.


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)

Attenuation of hepatic leptin signaling results in increased insulin-stimulated phosphorylation of Akt in the liver. Following the hyperinsulinemic-euglycemic clamp, liver tissues were harvested and flash-frozen. Liver lysates were prepared and Western blots performed for phosphorylated and total Akt levels. Representative blots from two Leprflox/flox Albcre tg− and two Leprflox/flox Albcre tg+ mice are shown in A. Quantification of all samples by densitometry is shown in B, n ≥ 8. Data are mean ± SEM. p-Akt, phosphorylated Akt.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 7: Attenuation of hepatic leptin signaling results in increased insulin-stimulated phosphorylation of Akt in the liver. Following the hyperinsulinemic-euglycemic clamp, liver tissues were harvested and flash-frozen. Liver lysates were prepared and Western blots performed for phosphorylated and total Akt levels. Representative blots from two Leprflox/flox Albcre tg− and two Leprflox/flox Albcre tg+ mice are shown in A. Quantification of all samples by densitometry is shown in B, n ≥ 8. Data are mean ± SEM. p-Akt, phosphorylated Akt.
Mentions: To more specifically explore insulin sensitivity at the level of the liver in male mice, hyperinsulinemic-euglycemic clamp studies were performed. Figure 6A and B shows that hyperinsulinemia was achieved while maintaining euglycemia during the clamp, and that no differences in blood glucose or plasma insulin levels were observed between Leprflox/flox Albcre tg+ and their Leprflox/flox Albcre tg− littermate controls. In the basal (non-hyperinsulinemic) state, whole-body glucose utilization and endogenous glucose production were similar for the Leprflox/flox Albcre tg+ and Leprflox/flox Albcre tg− littermate controls (Fig. 6C). As expected, in both Leprflox/flox Albcre tg+ and Leprflox/flox Albcre tg− mice, glucose utilization increased and endogenous glucose production decreased in the hyperinsulinemic phase. While whole-body glucose utilization was similar between the mice with and without hepatic leptin signaling, there was a significant difference in insulin-induced suppression of endogenous glucose production (P = 0.03). In the littermate controls, insulin suppressed glucose production by 39%, while in the Leprflox/flox Albcre tg+ mice, insulin suppressed glucose production by 68%. Since the majority of endogenously produced glucose comes from hepatocytes, these data provide evidence that a loss of hepatic leptin signaling mediates enhanced insulin sensitivity in the liver. This notion is supported by our finding that levels of phosphorylated Akt, a key mediator of insulin signaling, was increased in mice lacking hepatic leptin signaling when compared with littermate controls (Fig. 7). Taken together, our data suggest that a loss of hepatic leptin signaling leads to increased insulin sensitivity in the liver.

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