Abstract
The relative contribution of peripheral and central leptin signalling to the regulation of metabolism and the mechanisms through which leptin affects glucose homeostasis have not been fully elucidated. We generated complementary lines of mice with either leptin receptor (Lepr) knockdown or reconstitution in adipose tissues using Cre-lox methodology. Lepr knockdown mice were modestly lighter and had lower plasma insulin concentrations following an oral glucose challenge compared to controls, despite similar insulin sensitivity. We rendered male mice diabetic using streptozotocin (STZ) and found that upon prolonged leptin therapy, Lepr knockdown mice had an accelerated decrease in blood glucose compared to controls that was associated with higher plasma concentrations of leptin and leptin receptor. Mice with transcriptional blockade of Lepr (LeprloxTB/loxTB) were obese and hyperglycemic and reconstitution of Lepr in adipose tissues of LeprloxTB/loxTB mice resulted in males reaching a higher maximal body weight. Although mice with adipose tissue Lepr reconstitution had lower blood glucose levels at several ages, their plasma insulin concentrations during an oral glucose test were elevated. Thus, attenuation or restoration of Lepr in adipocytes alters the plasma insulin profile following glucose ingestion, modifies the glucose-lowering effect of prolonged leptin therapy in insulin-deficient diabetes, and may modulate weight gain.
Highlights
Multiple studies have reported that leptin action in the central nervous system (CNS) is critical for its regulation of food intake, thermogenesis, glucose homeostasis, and insulin sensitivity[1,2,3,4,5,6,7,8]
We found that Cre-mediated excision of leptin receptor (Lepr) in adipose tissues modestly decreased body weight and diminished the insulin response during an oral glucose challenge in male and female mice
In the setting of insulin-deficiency, male mice with Lepr knockdown had an accelerated glucose-lowering response to prolonged leptin administration compared to controls that was associated with increased concentrations of plasma leptin and leptin receptor
Summary
Multiple studies have reported that leptin action in the central nervous system (CNS) is critical for its regulation of food intake, thermogenesis, glucose homeostasis, and insulin sensitivity[1,2,3,4,5,6,7,8]. Using antisense RNA expressed under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, Huan et al.[13] downregulated expression of leptin receptor isoforms in mouse white adipose tissue (WAT). This resulted in obesity, insulin resistance, glucose intolerance, and ectopic fat accumulation. Wang et al.[15] reported that overexpression of Leprb in adipose tissue using an aP2 promoter inhibited the elevation in body weight caused by high fat diet, but these alterations may not have been adipose tissue-specific because subsequently, studies with aP2-Cre mice found Cre-mediated recombination in non-adipose tissues[16]. Our objective was to clarify the role of adipose tissue leptin signalling in metabolism using two complementary approaches based on Cre-lox methodology: generating mice lacking Leprb in adipose tissues and mice that express Leprb only in adipose tissues
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