Abstract
BackgroundTestosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling. Furthermore, physiological blood concentrations of testosterone have been found to inhibit the development of arteriosclerosis, obesity and diabetes. However, these findings have not been verified by testosterone replacement in animal models and whether or not testosterone acts directly by activating AR to enhance leptin signaling, or indirectly by its conversion into estrogen remains unclear. Therefore, we investigated the effect of exogenously supplemented testosterone on glucose and lipid metabolism.MethodsFour-week-old male leptin receptor-knockout db/db mice were used as controls for a model of obesity retaining low testosterone. Mice were divided into sham-operated, castrated, or castrated and testosterone-supplemented groups and fed a high-fat diet (HFD) for 2 weeks from 5 weeks of age. Testosterone concentrations, blood glucose, plasma insulin levels, and intraperitoneal glucose tolerance and insulin tolerance were measured. At 7 weeks, triglyceride and glycogen content were measured in the liver and muscle. Lipid accumulation in the liver and soleus muscle was determined by immunohistochemistry with Oil Red O. Statistical analyses were performed using the Student’s t-test or ANOVA where applicable.ResultsLower testosterone levels in db/db mice compared with wild type (WT) db/+ mice were associated with glucose intolerance and fatty liver. Furthermore, castrated male db/db mice at 4 weeks of age progressively developed glucose intolerance accompanying a 15% increase in liver fat. Male mice fed a HFD had lower levels of testosterone compared with those fed a normal diet. We found that exogenous testosterone replacement injected subcutaneously into castrated male db/db mice alleviated the exacerbation of fatty liver and glucose intolerance, suggesting a leptin-independent mechanism. This mechanism is most likely mediated through gonadal axis suppression in this mouse model.ConclusionsIn summary, testosterone may use a novel pathway to complement leptin signaling to regulate glucose and lipid metabolism, and thus offers a new therapeutic target to treat metabolic disorders.
Highlights
Testosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling
A decrease in blood testosterone levels was recently shown to increase the incidence of all-cause mortality [4], in addition to metabolic syndrome (MetS) [5,6,7], type 2 diabetes [8,9,10] associated with the progression of visceral obesity and enhancement of insulin resistance, osteoporosis-associated fracture [11,12,13], and progression of arteriosclerosis [14,15,16]
Influence of obesity and fatty foods on low circulating testosterone levels in mice A significant decrease in blood testosterone levels was observed in the order: high-fat diet (HFD)-fed db/db > normal chow diet (NCD)-fed db/db > NCD-fed db/+ mice (Fig. 1a), which was consistent with the order of glucose intolerance observed in response to Intraperitoneal glucose tolerance test (ipGTT) and assessed by measurement of glucose area under curve (AUC) (Fig. 1b)
Summary
Testosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling. Physiological blood concentrations of testosterone have been found to inhibit the development of arteriosclerosis, obesity and diabetes. These findings have not been verified by testosterone replacement in animal models and whether or not testosterone acts directly by activating AR to enhance leptin signaling, or indirectly by its conversion into estrogen remains unclear. A decrease in blood testosterone levels was recently shown to increase the incidence of all-cause mortality [4], in addition to metabolic syndrome (MetS) [5,6,7], type 2 diabetes [8,9,10] associated with the progression of visceral obesity and enhancement of insulin resistance, osteoporosis-associated fracture [11,12,13], and progression of arteriosclerosis [14,15,16]. Whether a low testosterone level may be a potent predictor of clinically-important coronary arterial disease has not been confirmed in previous case-controlled and longitudinal studies [18, 19]
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