Potential adverse effects of botanical supplementation in high-fat-fed female mice

Abstract

BackgroundInsulin resistance underlies metabolic syndrome and is associated with excess adiposity and visceral fat accumulation, which is more frequently observed in males than females. However, in young females, the prevalence of metabolic syndrome is rising, mainly driven by accumulation of abdominal visceral fat. The degree to which sex-related differences could influence the development of insulin resistance remains unclear, and studies of potential therapeutic strategies to combat metabolic syndrome using rodent models have focused predominantly on males. We therefore evaluated the effects of two nutritional supplements derived from botanical sources, an extract of Artemisia dracunculus L. (termed PMI5011) and Momordica charantia (commonly known as bitter melon), on female mice challenged with a high-fat diet in order to determine if dietary intake of these supplements could ameliorate obesity-induced insulin resistance and metabolic inflexibility in skeletal muscle.MethodsBody composition, physical activity and energy expenditure, fatty acid oxidation, insulin signaling, and gene and protein expression of factors controlling lipid metabolism and ectopic lipid accumulation were evaluated in female mice fed a high-fat diet supplemented with either PMI5011 or bitter melon. Statistical significance was assessed by unpaired two-tailed t test and repeated measures ANOVA.ResultsPMI5011 supplementation resulted in increased body weight and adiposity, while bitter melon did not induce changes in these parameters. Pyruvate tolerance testing indicated that both supplements increased hepatic glucose production. Both supplements induced a significant suppression in fatty acid oxidation in skeletal muscle homogenates treated with pyruvate, indicating enhanced metabolic flexibility. PMI5011 reduced lipid accumulation in skeletal muscle, while bitter melon induced a downward trend in lipid accumulation in the skeletal muscle and liver. This was accompanied by transcriptional regulation of autophagic genes by bitter melon in the liver.ConclusionsData from the current study indicates that dietary supplementation with PMI5011 and bitter melon evokes a divergent, and generally less favorable, set of metabolic responses in female mice compared to effects previously observed in males. Our findings underscore the importance of considering sex-related variations in responses to dietary supplementation aimed at combating metabolic syndrome.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0199-1) contains supplementary material, which is available to authorized users.

Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose

“…While fatty acid oxidation was increased by the HFS diet, fatty acid oxidation was not suppressed by pyruvate, suggesting the elevated dietary intake of fat and sucrose induced metabolic inflexibility in skeletal muscle of the females. Unlike our previously reported findings in females fed a high fat diet [22], botanical supplementation in conjunction with an HFS diet did not shift skeletal muscle toward carbohydrate oxidation when challenged with pyruvate. Figure 3.…”

“…Given the rising prevalence of MetS in women and data indicating that women use dietary supplements at higher rates than men [53][54][55], we asked whether botanical supplements reported to improve glucose homeostasis and reduce ectopic lipid accumulation [14,16,25,56,57] would modulate the metabolic effects of the HFS diet in females. We previously reported that female mice respond in a generally less advantageous manner to botanically derived nutritional supplements than males in the context of a high-fat diet [22]. However, botanical supplementation in this cohort of female mice evoked a set of metabolically beneficial responses compared to HFS diet alone that were independent of changes in body weight.…”

“…Mixed gastrocnemius muscle homogenates were prepared as described [22]. Palmitate oxidation was assessed in the whole-muscle homogenates as described by Hulver et al [30] with 14 CO 2 collected over 60 min.…”

“…Additional studies in male rodents showed that Momordica charantia, commonly known as bitter melon, acts as an insulin sensitizer by diminishing hepatic and skeletal muscle lipid accumulation and by reducing hepatic glucose production and lipogenesis [17][18][19][20]. Although these studies support the idea that botanical dietary supplements derived from sources such as Artemisia dracunculus L. and Momordica charantia can exert metabolically desirable effects in male mice exhibiting the risk factors for MetS [16,21], the beneficial effects may not be recapitulated in female mice exposed to a high-fat diet [22].…”

Designing a Clinical Study With Dietary Supplements: It's All in the Details

“…To better align with the clinical picture of MetS, later preclinical experiments were carried out in a rodent model of obesity-induced insulin resistance ( 15 , 16 ). However, the insulin resistance phenotype in the C57BL/6 mouse model of obesity-induced insulin resistance occurs in obese male, but not female mice when fed a defined high fat diet ( 17 ).…”