Sex Differences in Metabolism Following a High-fat Meal

Long-term consumption (i.e., several weeks to months) of a diet that is high in fat (\>35% daily calories from fat) is associated with the development of insulin resistance, a condition that can lead to a diagnosis of type 2 diabetes. Women tend to be better protected against the development of high-fat diet-induced insulin resistance compared with men, but it is not fully understand why this sex difference exists. It is possible that women metabolize high-fat meals differently than men, which might explain why they are less likely to develop type 2 diabetes over the course of their lifetime. However, no one has ever compared the metabolic response to a high-fat meal between men and women in the hours immediately after ingestion.

During this study, the investigators will administer a single high-fat "fast-food" style breakfast meal (846 kcal, of which 58% is fat) to 24 health young adults (n=12 men, n=12 women) 18-35 years old. Their objective is to determine whether there are differences in the way men and women metabolize high-fat meals, such as this one. The research team will take regular blood samples after participants ingest this meal to measure features of glucose metabolism (e.g., blood glucose and insulin) as well as resting oxygen uptake (VO2) measurements to examine how much of this meal is burned for energy in the hours immediately after ingestion.

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)

The investigators hypothesize that, compared with males, females will demonstrate:

1. Lower circulating concentrations of glucose, insulin, c-peptide and glucagon
2. Lower circulating concentrations of triglycerides, total cholesterol, low-density lipoprotein cholesterol and NEFAs; and higher circulating concentrations of high-density lipoprotein cholesterol
3. Greater energy expenditure and fat oxidation, and lower carbohydrate oxidation

This acute nutrition intervention study will involve a total of 3 visits to the laboratory (initial screening visit plus 2 study visits). After a screening visit to assess eligibility, young adults who have consented to participate will report to the laboratory after an overnight on 2 separate occasions: Baseline Assessment (Visit 1) and Nutrition Intervention (Visit 2).

Screening visit: Eligibility will be assessed during a screening session at the laboratory. The investigators will measure body mass, height, and resting blood pressure. Members of the research team will also help potential participants complete a Current Health Status Questionnaire, which will assess the potential participant's age, self-reported physical activity levels, and any medications or medical conditions that are relevant to the study.

Visit 1: Baseline Assessment: Participants will be asked to arrive after an overnight fast (i.e., no food or drink except for water for 8-12 hours). First, the investigators will perform a finger prick assessment to confirm eligibility and then evaluate body composition using dual-energy X-ray absorptiometry (DXA). Participants will be provided with a 3-day food diary and activity monitor at the conclusion of Visit 1, along with instructions on how to complete both.

Visit 2: Nutrition Intervention: After an overnight fast, participants will be asked to consume the high-fat test meal. The high-fat test meal will consist of bacon, eggs, cheese, tortilla, hashbrowns and mayonnaise (846 kcal, 58% fat, 29% carbohydrate, 13% protein). Members of the research team will prepare the meals in our metabolic kitchen. Before and after the meal is consumed, the researchers will take a series of blood samples and perform repeated resting VO2 measurements.

Eligibility Criteria:
Inclusion Criteria:

* BMI between 18.5 and 30.0 kg/m2
* Weight stable for the past 6 months (± 2kg)
* Exercise at or below the Canadian Physical Activity Guidelinesa
* Fasting blood glucose \<6.0 mM
* Resting blood pressure \<140/90 mmHg
* No hormone-altering contraceptive use (e.g., pill, patch, ring, injection)

Exclusion Criteria:

* Smoking
* Diabetes, cancer, or other metabolic disorders
* Cardiac or gastrointestinal problems
* Infectious disease
* Barium swallow or nuclear medicine scan in the previous 3 weeks
* Pregnant or breastfeeding
* Diagnosis of polycystic ovary syndrome
* Follow a vegan or vegetarian diet
* Not fully vaccinated against COVID19