The global obesity epidemic fuels the ongoing debate on the relative roles of dietary fat and carbohydrates. Two main models attempt to explain this: the energy balance model (EBM) and the carbohydrate-insulin model (CIM). EBM posits that obesity results from a calorie imbalance, irrespective of macronutrient source. The readily available, energy-dense, ultra-processed foods in modern diets contribute to this imbalance. CIM, conversely, emphasizes the role of refined carbohydrates, particularly sugars, in triggering a hyperinsulinemic response, leading to increased fat storage and appetite stimulation. While both models acknowledge the importance of sugars, they diverge on the role of fat. EBM implicates fat's high energy density and palatability, while CIM suggests that replacing carbohydrates with fat reduces postprandial glycemic and insulinemic responses, thereby decreasing fat storage. However, the prevalence of ultra-processed foods, often rich in both fat and sugars, complicates isolating the effects of each macronutrient. This research utilizes a multi-nutrient approach, focusing on the fat-sugar interaction using nutritional geometry (NG), to overcome this limitation and clarify the metabolic effects of fat independent of its caloric density. Previous research using NG explored contradictions in carbohydrate types and their interaction with protein on metabolic health. This study builds upon that work by investigating the interplay between fat and sugar composition to resolve discrepancies between EBM and CIM.

Existing literature highlights the substantial impact of dietary fats and carbohydrates on metabolic health and the controversy surrounding their roles in obesity. Studies have shown that carbohydrates, particularly those with high glycemic indexes, can lead to rapid spikes in blood glucose and insulin, promoting fat storage. Meanwhile, high-fat diets, while energy-dense, are associated with satiety and potentially have benefits when replacing carbohydrates. The EBM and CIM represent contrasting viewpoints. EBM emphasizes energy balance as the primary determinant of obesity, regardless of macronutrient source. CIM, however, emphasizes the impact of high glycemic carbohydrates and insulin resistance, and potentially downplays the impact of fat in causing obesity. The complexity of this debate is amplified by the combination of both fats and sugars found in modern ultra-processed foods. A comprehensive review of relevant studies on the metabolic effects of dietary fat and various carbohydrates is needed to provide a background for the current experimental study design and the expected outcomes.

This study employed nutritional geometry (NG) to systematically investigate the interaction between dietary fat and sugars (fructose and glucose) on metabolic outcomes in male C57BL/6J mice. A total of 245 mice were randomly assigned to one of 18 isocaloric diets (-14.3 kJ/g) with varying compositions. Protein was held constant at 20% of total energy. Dietary fat content was manipulated across three levels: low (10%), medium (20%), and high (30%). The remaining energy was allocated to carbohydrates, including a fixed proportion of native wheat starch (30%) and varying amounts of fructose and glucose. Fifteen of the 18 diets used soy oil as the fat source; the remaining three used lard. The fructose-to-glucose ratio ranged from 100:0 to 0:100. Mice were fed ad libitum for 18–19 weeks, with metabolic assessments at weeks 5-6 and 12-14. In vivo measurements included body composition (MRI), energy expenditure (indirect calorimetry), glucose tolerance tests (GTT), and insulin tolerance tests (ITT). Following euthanasia, liver samples were collected for analysis of hepatic fat content, histological examination, and gene expression analysis (qPCR) of relevant metabolic pathways (e.g., de novo lipogenesis). Blood samples were also analyzed for insulin and fibroblast growth factor 21 (FGF21) levels and plasma triglyceride levels. Data analysis utilized generalized additive modeling (GAM) within the NG framework to assess the effects of nutrient interactions on various metabolic parameters.

The study's key findings demonstrate a complex interplay between dietary fat and sugar composition. Mice consuming a 50:50 mixture of fructose and glucose exhibited the highest energy intake, body weight, and adiposity at low-to-medium fat levels (10-20%). This effect was independent of caloric intake. This 50:50 mixture, resembling high-fructose corn syrup (HFCS), was also found to increase hepatic fat content more strongly than consuming glucose or fructose alone, suggesting that it causes increased de novo lipogenesis. However, as dietary fat content increased to 30%, the effects of the 50:50 fructose-glucose mixture on body weight and adiposity were less pronounced. This suggests that the effect of high dietary fat is more impactful than the effect of the specific sugars in the diet. High fat intake universally impaired glucose homeostasis, independent of sugar composition, significantly reducing insulin sensitivity and glucose tolerance. The source of fat (soy oil vs. lard) did not significantly alter these outcomes. Hepatic expression of de novo lipogenic genes (e.g., *Acly*, *Fasn*) was highest in mice consuming high fructose diets at low-to-medium fat levels, while the expression decreased with increased dietary fat, suggesting that the impact of de novo lipogenesis in the liver is reduced as dietary fat intake increases. Conversely, expression of the pro-inflammatory gene *Mcpt1* increased with high fat intake.

The study's findings offer a nuanced perspective on the 'carbohydrate vs. fat' debate by demonstrating context-dependent effects. At lower fat intakes, the 50:50 fructose-glucose mixture promoted greater calorie intake, supporting aspects of the EBM. However, at higher fat intakes, the detrimental effects on glucose tolerance and insulin sensitivity are more pronounced, regardless of the sugar mix, indicating that high fat intake has a far more detrimental effect on insulin sensitivity. This supports components of the CIM, as it is the higher carbohydrate intake that resulted in increased liver fat content. These findings reconcile elements of both EBM and CIM, highlighting the influence of both caloric intake and macronutrient composition on metabolic outcomes. The observation that higher fat intake, regardless of sugar composition, causes detrimental metabolic changes underscores the importance of considering the complete dietary context. This study challenges the simplistic notion of 'good' versus 'bad' fats and sugars and highlights the need for a more comprehensive nutritional approach.

This study demonstrates that a 50:50 fructose-glucose mixture is more obesogenic than consuming either monosaccharide alone, particularly at lower dietary fat levels. However, high fat intake generally overrides the effects of sugar composition, leading to widespread metabolic dysfunction. These findings highlight the limitations of single-nutrient approaches and underscore the need for a more holistic understanding of dietary interactions in obesity development. Future research should focus on complex carbohydrates and the effects of liquid vs solid carbohydrate consumption. Also, exploring the impact of other dietary factors and genetic variation are warranted.

The study's limitations include the use of a single strain of male mice, excluding the potential for sex-specific effects or differences in other genetic backgrounds. The study did not test complex carbohydrates, the effects of sugars in liquid form (which is common in human diets) or under thermoneutral conditions. Furthermore, the study did not directly measure postprandial glycemic and insulinemic responses, hypothalamic appetite signaling, or perform pair-feeding experiments. While these limitations are acknowledged, the study provides crucial insights into the interactions between dietary fats and sugars, informing future research.