Sex-Specific Differences in Fat Storage, Development of Non-Alcoholic Fatty Liver Disease and Brain Structure in Juvenile HFD-Induced Obese Ldlr-/-.Leiden Mice

Abstract

Background: Sex-specific differences play a role in metabolism, fat storage in adipose tissue, and brain structure. At juvenile age, brain function is susceptible to the effects of obesity; little is known about sex-specific differences in juvenile obesity. Therefore, this study examined sex-specific differences in adipose tissue and liver of high-fat diet (HFD)-induced obese mice, and putative alterations between male and female mice in brain structure in relation to behavioral changes during the development of juvenile obesity. Methods: In six-week-old male and female Ldlr-/-.Leiden mice (n = 48), the impact of 18 weeks of HFD-feeding was examined. Fat distribution, liver pathology and brain structure and function were analyzed imunohisto- and biochemically, in cognitive tasks and with MRI. Results: HFD-fed female mice were characterized by an increased perigonadal fat mass, pronounced macrovesicular hepatic steatosis and liver inflammation. Male mice on HFD displayed an increased mesenteric fat mass, pronounced adipose tissue inflammation and microvesicular hepatic steatosis. Only male HFD-fed mice showed decreased cerebral blood flow and reduced white matter integrity. Conclusions: At young age, male mice are more susceptible to the detrimental effects of HFD than female mice. This study emphasizes the importance of sex-specific differences in obesity, liver pathology, and brain function.

Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH)

“…(42) Indeed, liver physiopathological responses to various challenges are sex dependent in rodents. (47)(48)(49) Although the translatability of these findings to our human-based analysis is not straightforward, all these data converge toward a definition of human NASH as a sexually dimorphic disease. This is a potentially important and relevant finding in terms of biomarker research (given that, e.g., YKL-40/CHI3L1 is included in a biomarker panel in development), as well as for risk stratification and pharmacological therapy.…”

Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine

“…Paraffin-embedded cross-sections (5 μm) of the epididymal and the mesenteric white adipose tissue were stained with hematoxylin-phloxine-saffron and digitised using a slide scanner (Aperio AT2, Leica Biosystems, Amsterdam, the Netherlands). Adipose tissue morphometry (average adipocyte size and adipocyte size distribution) and inflammation (number of crown-like structures; CLS per 1000 adipocytes) were analysed as described previously ( 35 ), using the automated image analysis software Adiposoft for morphometry analyses ( 36 ) and counting the number of CLS in the same fields used for morphometry analyses. Formalin-fixed and paraffin-embedded cross-sections of the medial liver lobe (3 μm) were stained with haematoxylin and eosin and scored blindly by a board-certified pathologist using an adapted grading method for human NASH ( 37 , 38 ) as described previously ( 39 ).…”

Diet and exercise reduce pre-existing NASH and fibrosis and have additional beneficial effects on the vasculature, adipose tissue and skeletal muscle via organ-crosstalk

“…In the present study we investigated the effect of lifestyle interventions on NASH in Ldlr−/−.Leiden mice, a well-established model for hyperlipidemia and atherosclerosis that develop NASH with advanced fibrosis when fed a high fat diet [13][14][15][16][17][18][19][20][21][22]. The model has been proven to be responsive to several nutritional and pharmacological interventions [15,17,18,20,21,[23][24][25].…”