Dietary Fructose: a Metabolic Switch in Pediatric Obesity-related Disease.

Evaluation of Liver and Osteo-metabolic Complications Related to the Consumption of Fructose in a Cohort of Overweight and Obese Children and Adolescents.

The increase in childhood obesity is a multifactorial phenomenon influenced by dietary patterns, commercial factors, and social determinants; it has long-term consequences for both individual health and society as a whole. Despite recommendations for maintaining good health throughout life and promoting the Mediterranean Diet, due to the increased availability of ultra-processed and more appealing foods, children and adolescents are shifting towards a "Western" diet. One in four children consumes sugary and carbonated drinks every day, which contributes to a high intake of fructose in the diet, while fruits and vegetables are consumed less, and legumes are included in the diet of only 38% of children less than once a week.

Fructose is a monosaccharide naturally found in fruits, vegetables, and honey; due to its high sweetness and taste-enhancing properties, fructose is widely used in the food industry. High-fructose corn syrup, in particular, is one of the most widely used ingredients in the production of soft drinks, jams, breakfast cereals, and bakery products. Non-alcoholic fatty liver disease (NAFLD), now also called metabolic dysfunction-associated fatty liver disease (MAFLD), is considered the hepatic manifestation of metabolic syndrome and currently represents the most common chronic liver disease in pediatric age in Western countries. Recent studies suggest that fructose consumption is implicated in the development of NAFLD both directly by providing metabolites that can be used for triglyceride and free fatty acid synthesis, and indirectly through increased uric acid production. High-fructose foods also appear to be a risk factor for bone loss. Numerous studies conducted over the past 25 years, during which fructose consumption has exponentially increased, have shown that this sweetener tends to increase the incidence of fractures and osteoarthritis and decrease bone mineral density (BMD) and new bone tissue deposition.

The objective of this study is to understand the effect of fructose on the molecular events that contribute to the evolution of the pediatric age, and its effective relationship with the onset of liver and osteoarticular complications in this population. Understanding the mechanisms of fructose regulation and its effects on the body could be an important target to address the clinical and social problems arising from its spread in children.

At the time of recruitment, patients referred to the Endocrinology Outpatient Clinic of the AOU (Azienda Ospedaliera Universitaria) Maggiore della Carità in Novara, the Transition Endocrinology Outpatient Clinic of the Endocrinology SCDU (Struttura Complessa a Direzione Universitaria), and the Pediatric Endocrinology Outpatient Clinic "B. Trambusti" of the Giovanni XXIII Pediatric Hospital, will undergo:

Questionnaires to assess the quantity of fructose intake through diet:

• KIDMED (quality index for children and adolescents) questionnaire to evaluate adherence to the Mediterranean diet in children/adolescents.
• IDEFICS (Identification and preven- tion of Dietary- and lifestyle- induced health EFfects In Children and infantS) questionnaire to assess food frequency in children.
• 24-hour recall questionnaire to gather information about meals consumed in the previous 24 hours. Macronutrient quantities will be obtained using dedicated software, "Professional Diet Therapy Software Dietosystem" from DSMedica(industry supplying the software). The questionnaire includes specific questions and figures to identify food portions and relate them to the quantity of fructose consumed.
• Calculation of the Dietary Inflammatory Index (DII) through a list of foods. This parameter allows for the determination of how much a dietary pattern promotes the synthesis of pro-inflammatory molecules.
• Sociological questionnaire prepared ad hoc by Unit 3 to assess dietary habits and fructose intake in relation to the family's socioeconomic status.

Anamnestic evaluation:

• The mother of the patient will be asked for gestational age, mode of delivery, and the child's birth anthropometric data.
• Recording of current pharmacological therapy (if present).

Instrumental evaluation:

• Quantitative and qualitative analysis of bone composition using quantitative ultrasound (QUS). This tool provides various parameters related to bone composition, specifically speed of sound (SOS) for bone density evaluation, broadband ultrasound attenuation (BUA) for trabecular structure evaluation, ultrasound peak amplitude for trabecular size evaluation, number of peaks for connectivity evaluation of the mineralized matrix structure, and energy and amplitude of fast waves for elasticity evaluation.
• Abdominal ultrasound (US) to assess hepatic steatosis, perivisceral and subcutaneous fat. The presence of hepatic steatosis (NAFLD) will be classified from stage 1 to stage 3 according to the literature.

Clinical-auxological evaluation:

• Anthropometric measurements including weight, height, and BMI according to STANDARD DEVIATION SCORE (SDS).
• Waist and hip circumference measurements.
• Measurement of blood pressure and heart rate.
• Analysis of body composition through bioimpedance analysis (BIA).

Expected results With this study, the investigators expect to acquire new knowledge about the effect of fructose on the onset of obesity-associated liver disease (NAFLD) and bone metabolism, by identifying new biological, immunological, and omics markers that can be studied in the future as disease targets in the pediatric population. Furthermore, due to scientific and sociological interest, this study aims to identify sociodemographic and cultural determinants related to fructose intake, which will be useful for creating preventive campaigns aimed at promoting a healthy lifestyle. This includes changing dietary habits to encourage a healthy diet and reducing obesity in the population.

Inclusion Criteria:

• Children and adolescents of both sexes aged 3-6 years and 12-16 years, as interest groups for the assessment of hepatic steatosis induced by fructose consumption.
• Children with overweight (defined by BMI > 97 year old percentile for children under 5 years old; and BMI >85 year old percentile for children over 5 years old) or obesity (defined by BMI > 99 percentile for children under 5 years of age; and BMI > 97 percentile for children over 5 years of age)

Exclusion Criteria:

• Children and adolescents not in that age group:
• Children and adolescents with different liver diseases of NAFLD, as it is the interest of the study
• Children and adolescents with genetic obesity or secondary obesity since the interest of the study is obesity caused by excessive calorie intake
• Children and adolescents included in diet-therapy regimen with different dietary styles from the Mediterranean or Western diet (example ketogenic diet, FoadMap (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, vegan/vegetarian diet) to avoid bias in the interpretation of the microbial signature (the microbial signature of the Western and Mediterranean diet is known in the literature);