Exploring Sex Differences in the Acute Postprandial Metabolic Response to a High-fat Mixed Macronutrient Meal Challenge in Healthy Young Humans

Long-term high-fat feeding is known to induce insulin resistance and impair whole-body glucose clearance in humans, yet knowledge of the glucose metabolic effects of high-fat feeding remains incomplete. Excess fat consumption leads to elevated circulating concentrations of non-esterified fatty acids (NEFAs), which (when taken up by muscle, an organ vital for glucose homeostasis) may interfere with insulin signaling and glucose disposal.

Despite the relatively rich body of research on high-fat feeding, the acute (i.e., 1-4 hours post-ingestion) effects of a high-fat meal on postprandial glucose metabolism are poorly characterized. Understanding the acute response to high-fat feeding is a key step towards uncovering the mechanisms that drive the development of dietary fat-induced insulin resistance. Limited work suggests that postprandial insulinemia may be elevated in response to a high-fat meal, and that this effect may be more pronounced in individuals with higher adiposity. Previous work has shown that ingestion of a mixed macronutrient meal high in saturated fat (~60% total fat, 32% saturated fat) stimulated significantly greater increases in circulating insulin concentrations in obese compared with lean middle-aged subjects. The effect of acute high-fat feeding on postprandial glycemia is less clear: studies have reported increased, decreased, or no change in glucose concentrations in response to a high-fat challenge. The quantity of fat administered may help explain these conflicting reports: studies have variously employed meals comprising 40%, 60% and up to 80% fat. These discrepancies in the literature may also be underpinned by the inclusion of males and females in the same study.

There is a paucity of data on the glucose metabolic response to high-fat feeding in human females. Although a handful of studies have included female subjects, this may have masked potentially divergent effects of high-fat feeding on glucose metabolism in males compared with females. Generally speaking, females have lower fasting plasma glucose concentrations (indicative of heightened hepatic insulin sensitivity) and are more adept at storing circulating NEFAs as subcutaneous adipose tissue (SAT). Although males have greater skeletal muscle mass (an important glucose reservoir) and lower whole-body adiposity than females, they preferentially accumulate adipose tissue in depots associated with metabolic dysfunction, such as the viscera and skeletal muscle [30]. Indeed, only one study to date has directly compared males and females to show that 7 days of suprarenergetic high-fat feeding (+50% kcal/d, 65% fat) stimulated an increase in trunk fat mass in males, with no discernable body composition changes in females. Given these sex-based differences in insulin sensitivity and adipose tissue storage, it is possible that females exhibit a distinct glucose metabolic response to high-fat feeding compared to males. However, this hypothesis has yet to be fully explored.

Therefore, in this study, the investigators will administer a single high-fat mixed macronutrient meal to a group of healthy young adults. Over the 4-hour postprandial period, they aim to compare the following in females versus males:

1. Circulating features of glucose metabolism (primary objective)
2. Circulating features of lipid metabolism (secondary objective)
3. Energy expenditure and substrate oxidation via indirect calorimetry (tertiary objective)