Sex Hormones as Regulators of the Age- and Sex-dependent Benefits of Caloric Restriction

Official title

GendAge Weight Loss Study: Sex Hormones as Regulators of the Age- and Sex-dependent Benefits of Caloric Restriction

Overview

Obesity increases the risk of type 2 diabetes, cardiovascular disease, and certain cancers, primarily due to elevated abdominal fat storage. With nearly two-thirds of the UK population living with overweight or obesity, there is an urgent necessity for evidence-based public health guidance to promote healthy weight. Calorie deficit can facilitate weight loss and body fat reduction, leading to health benefits, such as improved blood glucose control. Current weight management advice centres on lifestyle modification, incorporating changes to diet and physical activity to support a calorie deficit. However, existing dieting recommendations fail to consider gender or age. This is a surprising oversight, as it is well established that health outcomes vary significantly between men and women across the lifespan. Further, the menopause may have an impact on fat storage linked to changes in sex hormones. Our recent research, involving both mice and humans, has indicated that females are less responsive to weight loss and fat reduction during dieting. This study aims to understand endocrine and metabolic sex-based differences in obesity and calorie restriction, with a particular focus on women's health. We plan to conduct a diet study with 75 participants, encompassing both younger and older men and women, to monitor changes in energy expenditure and body composition using gold-standard techniques, such as doubly-labelled water. Blood and abdominal fat tissue samples will be collected to investigate how sex hormones might elucidate these differences. The aim of the study is to enhance our understanding of diet and women's health to combat obesity and promote healthy ageing.

Interventions

• Other Phase 1 - Maintenance Diet
  3d maintenance diet (MT, fixed macronutrient composition of 15% protein, 30% fat and 55% CHO), fed to energy requirements (1.3 X RMR)
• Other Phase 2 - Weight loss diet
  6 week calorie restricted high protein diet (CR, fixed macronutrient composition as 30% protein, 35% fat and 35% CHO) fed to energy requirements \[0.8 X Resting Metabolic Rate (RMR)\], with stepwise reduction of 100kcal/d at week 3 and 5

Primary outcome measures

• Change in body mass expressed as weight in kilograms (kg) [Time frame: From baseline (day 1) to end of intervention (day 53); additional measurements taken three times a week throughout the intervention duration]
• Change in energy expenditure expressed in kilocalories per day (kcal/day) [Time frame: From day 11 (start of the calorie-restricted diet) to the end of the intervention (day 52); with additional doses consumed on day 25 and 39]

Secondary outcome measures (12)

• Change in resting metabolic rate (RMR) expressed in kcal/day [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53)]
• Change in bone mineral content in grams (g) [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53)]
• Change in total body water (TBW) in litres (l) [Time frame: From day 11 (start of the calorie-restricted diet) to end of the intervention (day 53)]
• Change in total body density expressed in litres (l) [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53)]
• Change in body fat-mass percentage (%) [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53)]
• Change in non-esterified fatty acids (NEFA) concentration in fasted blood sample [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53); also measured at midpoint of calorie-restricted diet (day 32)]
• Change in concentration of caloric-restriction (CR) related hormones in fasted blood sample [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53); also measured at midpoint of calorie restricted diet (day 32)]
• Change in sex hormones concentration in fasted blood sample [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53); also measured at midpoint of calorie restricted diet (day 32)]
• Body height measured in meters (m) [Time frame: Only at baseline]
• Change in Body Mass Index (BMI) expressed as kg/m^2 [Time frame: From baseline (day 1) to end of intervention (day 53); additional measurements taken three times a week throughout the intervention duration]
• Change in adipose tissue metabolism assessed by adipocite size [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53)]
• Change in adipose tissue metabolism assessed by phosphorylation of hormone-sensitive lipase (HSL) [Time frame: From day 8 (start of the maintenance diet) to end of the intervention (day 53)]

Eligibility criteria

Inclusion criteria

• Adults (aged over 18years) who are healthy but overweight/obese (BMI 27-45kg/m2) males and females as:
• 15 women (age 40 or less years)
• 15 men (age 40 or less years)
• 15 women (age 55-65 years) in menopause\*; not taking Hormone Replacement Therapy (HRT)
• 15 men (age 55-65 years)
• 15 women (age 55-65 years) in menopause; taking HRT\*\*

• menopause definition is no menstrual period for 12 months \*\*HRT inclusion criteria - women will have continuously taken oestrogen HRT for 24 months

Exclusion criteria

Potential volunteers will be asked to fill in a health questionnaire at the screening visit to assess their suitability for the study. This information will allow us to exclude participants.

Medication exclusion criteria, current use :-

• weight loss medication (e.g. GLP agonists), β-blockers, antihistamines, antipsychotics, benzodiazepines, barbiturates, melatonin, Ritalin, modafinil, soporifics, hypnotics, antiepileptic drugs, diabetes medication (e.g. metformin or insulin).

Self-reported medical exclusion criteria:

• Females who are planning to be pregnant, are pregnant or are breastfeeding
• Anyone with coeliac disease or gluten intolerance or food allergy
• Anyone with diagnosed T1 or T2 diabetes
• Anyone suffering from a psychiatric disorder or any type of substance abuse

Other exclusion criteria

• Anyone following a vegetarian or vegan diet
• Anyone currently following a weight loss programme (that may be affecting lifestyle, physical activity \& diet) or undergone gastric band/reduction surgery; including GLP agonist (e.g. Semaglutide injection, Ozempic®).
• Anyone currently participating in another research study
• Anyone with unsuitable veins for blood sampling
• Anyone who is unable to fluently speak, read and understand English
• Anyone who is unable to comply to an alcohol-free diet for 6 weeks
• Anyone unable to give fully informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Factorial

Masking

Open label

Primary purpose

Basic science

Study locations

United Kingdom · 1 center

• Rowett Institute, University of Aberdeen — Aberdeen

Identifiers

NCT: NCT07065643 · 822 · 2-034-25

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗