Leptospirosis is a widespread zoonotic disease caused by pathogenic spirochetes of the genus Leptospira which affect both humans and animals. A somewhat contradictory published body of evidence suggests that sex impacts severity outcomes of human Leptospirosis. In this study, we used an acute animal model of disease to analyze how male and female hamsters infected side-by-side with low but increasing doses of L. interrogans under the same exposure conditions develop Leptospirosis. We found that female hamsters were considerably more resistant to Leptospirosis given that 87.5% survived infection; male hamsters did not gain weight and 93.7% succumbed to infection with the same infectious doses. Analysis of bacterial burden in kidney of male hamsters showed that infection with the lowest dose (103) resulted in a 4Log increase of L. interrogans, whereas females infected with the same dose had a reduction of ~1Log, after 28 days of infection. Non-surviving hamsters had signs of compromised renal function (higher levels of creatinine in blood), as well as increased levels of anti-inflammatory IL-10 and innate response pro-inflammatory CCL3, CxCL10 and TNF-α in kidney, as well as ColA1 which is a marker of kidney fibrosis. In endemic areas, humans are more often exposed to the lower infection doses which were lethal to males, than the higher doses which were lethal to males and females. It is possible that the frequency of lower infectious doses in nature and increased biological susceptibility both contribute for aggravated outcomes of leptospirosis in males.
Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development.Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.
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