Maternally mediated and direct effects of fructose or artificial sweetener intake on metabolic and reproductive health

Abstract

Background: Growing rates of obesity and related comorbidities have resulted in increased awareness of the dangers posed by sugar-sweetened beverages. Artificial sweeteners (AS) such as acesulfame-K (Ace-K) are promoted as ‘healthier’ options compared to natural sweeteners and have risen in popularity in recent decades. This is despite evidence linking AS to obesity and metabolic disease. Limited information exists on the impact of AS intake on maternal health and that of offspring following exposure during pregnancy and lactation. Further, AS are often promoted to the weight conscious, yet studies examining the combination of AS with a high-fat diet (HFD) are limited and may increase the risk of adverse health outcomes. Aims: 1) Investigate the impact of Ace-K and fructose supplementation during pregnancy and lactation on maternal and offspring metabolic and reproductive health postpartum, as well as offspring skin integrity. 2) Investigate the effects of HFD and AS consumption on glucose homeostasis and adipose tissue physiology in male and female mice. Method: We utilised two animal models of altered nutrition: 1) altered maternal nutrition where C57BL/6 female mice received standard chow with water (CD), fructose, or Ace-K throughout pregnancy and lactation, and 2) C57BL/6 6-week-old male and female mice who received CD (CDCon), CD supplemented with Ace-K (CDAS), HFD with water (HFCon), or HFD with Ace-K (HFAS) for 6 weeks. Ace-K was selected as the AS given its common use in food and beverages, and the paucity of data on its effects in the setting of maternal nutrition. Maternal, offspring, and HFD-mice physiological measurements, metabolic profile, adipose tissue morphology and gene expression were assessed, as well as maternal and female offspring ovarian gene expression, female offspring estrus cyclicity, and offspring skin integrity. Results: In study one, AS and fructose supplementation induced a range of detrimental effects in postpartum dams including glucose intolerance, adipocyte hypertrophy, and alterations to ovarian genes associated with folliculogenesis. Female but not male offspring of Ace-K supplemented dams experienced glucose intolerance and increases in expression of ovarian genes related to ovulation. Maternal Ace-K and fructose intake disrupted female offspring estrus cycles, induced adipocyte hypertrophy in male and female offspring, and caused sex-specific responses to wound healing. In the second model, Ace-K improved male glucose tolerance alone and in conjunction with HFD, but not in female mice, who instead experienced increased expression of immune related genes. Conclusions: Our studies provide evidence that Ace-K may not be a heathier alternative to fructose in the maternal diet, following both direct and programming effects of intake in postpartum dams and offspring. Further, we showed that Ace-K exacerbates HFD-induced metabolic disease in a sex-specific manner. This work highlights the necessity of undertaking further research into the relative effects of AS and fructose intake in populations most at risk of metabolic and reproductive disturbances.