Reintroducing testosterone in the db/db mouse partially restores normal glucose metabolism and insulin resistance in a leptin-independent manner

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.Electronic supplementary materialThe online version of this article (10.1186/s12902-018-0266-y) contains supplementary material, which is available to authorized users.

Mice lacking the proton channel Hv1 exhibit sex-specific differences in glucose homeostasis

“…As shown in Figure 5 H , castration resulted in rising trend of glucose intolerance, but without a statistical significance. Previous studies also reported that the castration-induced testosterone deficiency results in an increase in fasting blood glucose levels, and reintroducing testosterone partly rescues normal glucose metabolism ( 22 , 23 ). These results demonstrated that the effect of physiological testosterone deficiency on metabolic disorders partly provides a basis for explaining the phenotype of KO mice.…”

Adenosine accumulation causes metabolic disorders in testes and associates with lower testosterone level in obese mice

“…Testosterone is a critical hormone in regulation of spermatogenesis (Walker, 2011). There is strong evidence of the negative effect of obesity on testosterone level (Craig et al, 2017; Yabiku et al, 2018).…”

“…The mechanisms by which obesity causes a decline in reproductive capacity are complex, involving endocrine disorders, inherited, physical, or chemical factors (Alves et al, 2016; Craig, Jenkins, Carrell, & Hotaling, 2017; Hayden, Flannigan, & Schlegel, 2018; Sifakis, Androutsopoulos, Tsatsakis, & Spandidos, 2017). Studies have shown that testosterone is reduced in obese men and animal models, which affects spermatogenesis (Craig et al, 2017; Yabiku, Nakamoto, & Tokushige, 2018). In addition, metabolic status is critical to controlling the energy requirements of the reproductive system, and metabolic disorders caused by obesity are detrimental to reproductive function (Dimopoulou, Goulis, Corona, & Maggi, 2018; Rato et al, 2012).…”

Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism

“…There is an interesting paradox that, in men, testosterone deficiency increases visceral fat content and insulin resistance; while in women, high androgen levels increase insulin resistance and visceral fat [30] . At the animal model, the testosterone levels of db/db mice were lower than that of the wild type mice, and exogenous testosterone replacement alleviated fatty liver of db/db mice [31] . Estrogen, another sex hormone, is one of the protective factors of NAFLD by suppressing lipid accumulation, inflammation and fibrosis [32] .…”