Periodic Reporting for period 1 - FoodBAT (Unraveling the interplay between food intake with endocrine factors in brown adipose tissue activation (FoodBAT))
Période du rapport: 2023-05-01 au 2025-05-31
Background /context
The global rise in obesity and cardiometabolic diseases has reached alarming proportions, with over 1 billion people expected to be obese by 2030. This escalating health crisis urgently requires innovative preventive and therapeutic strategies. Unlike white adipose tissue (WAT), brown adipose tissue (BAT) dissipates energy as heat, primarily through the action of uncoupling protein 1 (UCP-1). BAT acts as a metabolic sink, improving glucose and lipid clearance and offering a promising target in obesity management.
While cold exposure is a well-established BAT activator, recent evidence suggests that meal intake stimulates BAT thermogenesis via meal-induced thermogenesis (MIT). However, the mechanisms underlying this response, especially the role of gut-derived hormones, remain poorly understood in humans. Hormones such as secretin, GLP-1, GIP, and CCK have demonstrated BAT-activating potential in animal models, but their physiological relevance in human MIT is still largely unexplored.
The FoodBAT project aims to elucidate how food intake and endocrine factors interact to activate BAT under both thermoneutral and cold conditions, and how these processes are affected by obesity and modulated by a cold acclimation protocol (CA). Understanding these interactions could open new paths for nutritional, environmental, or pharmacological interventions targeting BAT to combat obesity and cardiometabolic diseases.
Hypotheses and objectives
We hypothesize that postprandial BAT activation in humans is modulated by a gut–BAT-brain axis initiated by food intake and gut hormone signaling, and that this pathway is partially impaired in obesity. Furthermore, we propose that a 3-month cold acclimation (CA) protocol can restore or enhance this axis in individuals with obesity. The project encompasses four interconnected work packages:
WP1 – Acute MIT Response: to investigate how a standardized mixed meal acutely modulates gut hormone secretion and its interplay with BAT metabolism in lean individuals and those with obesity under thermoneutral versus cold conditions.
WP2 – Cold Acclimation intervention: to understand how a 3-month cold acclimation protocol (18°C water immersion, twice weekly) alters endocrine responses, BAT activation, and MIT in individuals with obesity.
WP3 – Gut–Brain–BAT Axis: to explore the relationship between postprandial hormonal responses and BAT perfusion in response to a mixed meal using PET/CT imaging, indirect calorimetry, and hormonal/lipidomic profiling. Additionally, investigate the central nervous system's role in mediating BAT responses.
WP4—In Vitro Mechanisms: Brown adipocytes will be used to model the effects of nutrient stimuli, cold mimetics, and gut hormones on gene expression (UCP1, PGC-1α, etc.) and mitochondrial respiration. This will help dissect the cellular and molecular pathways underlying human MIT.
Methods
WP1 & WP2:
• The clinical trial included 52 participants (28 lean, 24 with obesity). Of the 56 volunteers enrolled, 52 completed at least two study visits.
• Volunteers underwent PET/CT scans with different radiotracers ([15O]H2O for tissue perfusion, [18F]FDG for glucose uptake, and [18F]FTHA for fatty acid uptake).
• Forty-six participants underwent MIT testing under warm and cold conditions using indirect calorimetry, and blood samples were drawn to assess metabolic and gut hormone profiles ( such as secretin, GLP-1, GIP, CCK).
• BAT and WAT biopsies from a subsample are being analyzed.
WP2
• Fourteen volunteers were included, and 11 participants with obesity finished a three-month cold acclimation protocol involving twice-weekly 18°C water immersions.
• Pre- and post-intervention assessments include the same MIT tests as WP1.
• Comparisons are under analysis to assess the effect of cold acclimation on MIT, hormone secretion, and BAT function.
WP3
• A proof-of-concept acute trial involving 30 volunteers (15 lean and 15 with obesity) will examine how postprandial endocrine responses correlate with BAT metabolism using PET/CT imaging and indirect calorimetry. Detailed hormonal and lipidomic profiles will be obtained multiple times after a mixed meal.
WP4
• Cell Studies (WP4): In vitro experiments with human brown adipocytes, examining hormonal and nutrient effects at the molecular level.
Innovation
FoodBAT is the first study to comprehensively investigate the interplay between food intake, appetite hormones, and BAT function in humans, across different physiological (thermoneutrality versus cold), pathophysiological (lean volunteers versus those with obesity), and cellular contexts. Its multidisciplinary approach integrates advanced imaging (PET/CT) clinical trials with blood markers and molecular biology.
By understanding how dietary and environmental factors modulate BAT via the gut–brain axis, FoodBAT could facilitate pharmacological and non-pharmacological interventions to improve metabolic health.
The global rise in obesity and cardiometabolic diseases has reached alarming proportions, with over 1 billion people expected to be obese by 2030. This escalating health crisis urgently requires innovative preventive and therapeutic strategies. Unlike white adipose tissue (WAT), brown adipose tissue (BAT) dissipates energy as heat, primarily through the action of uncoupling protein 1 (UCP-1). BAT acts as a metabolic sink, improving glucose and lipid clearance and offering a promising target in obesity management.
While cold exposure is a well-established BAT activator, recent evidence suggests that meal intake stimulates BAT thermogenesis via meal-induced thermogenesis (MIT). However, the mechanisms underlying this response, especially the role of gut-derived hormones, remain poorly understood in humans. Hormones such as secretin, GLP-1, GIP, and CCK have demonstrated BAT-activating potential in animal models, but their physiological relevance in human MIT is still largely unexplored.
The FoodBAT project aims to elucidate how food intake and endocrine factors interact to activate BAT under both thermoneutral and cold conditions, and how these processes are affected by obesity and modulated by a cold acclimation protocol (CA). Understanding these interactions could open new paths for nutritional, environmental, or pharmacological interventions targeting BAT to combat obesity and cardiometabolic diseases.
Hypotheses and objectives
We hypothesize that postprandial BAT activation in humans is modulated by a gut–BAT-brain axis initiated by food intake and gut hormone signaling, and that this pathway is partially impaired in obesity. Furthermore, we propose that a 3-month cold acclimation (CA) protocol can restore or enhance this axis in individuals with obesity. The project encompasses four interconnected work packages:
WP1 – Acute MIT Response: to investigate how a standardized mixed meal acutely modulates gut hormone secretion and its interplay with BAT metabolism in lean individuals and those with obesity under thermoneutral versus cold conditions.
WP2 – Cold Acclimation intervention: to understand how a 3-month cold acclimation protocol (18°C water immersion, twice weekly) alters endocrine responses, BAT activation, and MIT in individuals with obesity.
WP3 – Gut–Brain–BAT Axis: to explore the relationship between postprandial hormonal responses and BAT perfusion in response to a mixed meal using PET/CT imaging, indirect calorimetry, and hormonal/lipidomic profiling. Additionally, investigate the central nervous system's role in mediating BAT responses.
WP4—In Vitro Mechanisms: Brown adipocytes will be used to model the effects of nutrient stimuli, cold mimetics, and gut hormones on gene expression (UCP1, PGC-1α, etc.) and mitochondrial respiration. This will help dissect the cellular and molecular pathways underlying human MIT.
Methods
WP1 & WP2:
• The clinical trial included 52 participants (28 lean, 24 with obesity). Of the 56 volunteers enrolled, 52 completed at least two study visits.
• Volunteers underwent PET/CT scans with different radiotracers ([15O]H2O for tissue perfusion, [18F]FDG for glucose uptake, and [18F]FTHA for fatty acid uptake).
• Forty-six participants underwent MIT testing under warm and cold conditions using indirect calorimetry, and blood samples were drawn to assess metabolic and gut hormone profiles ( such as secretin, GLP-1, GIP, CCK).
• BAT and WAT biopsies from a subsample are being analyzed.
WP2
• Fourteen volunteers were included, and 11 participants with obesity finished a three-month cold acclimation protocol involving twice-weekly 18°C water immersions.
• Pre- and post-intervention assessments include the same MIT tests as WP1.
• Comparisons are under analysis to assess the effect of cold acclimation on MIT, hormone secretion, and BAT function.
WP3
• A proof-of-concept acute trial involving 30 volunteers (15 lean and 15 with obesity) will examine how postprandial endocrine responses correlate with BAT metabolism using PET/CT imaging and indirect calorimetry. Detailed hormonal and lipidomic profiles will be obtained multiple times after a mixed meal.
WP4
• Cell Studies (WP4): In vitro experiments with human brown adipocytes, examining hormonal and nutrient effects at the molecular level.
Innovation
FoodBAT is the first study to comprehensively investigate the interplay between food intake, appetite hormones, and BAT function in humans, across different physiological (thermoneutrality versus cold), pathophysiological (lean volunteers versus those with obesity), and cellular contexts. Its multidisciplinary approach integrates advanced imaging (PET/CT) clinical trials with blood markers and molecular biology.
By understanding how dietary and environmental factors modulate BAT via the gut–brain axis, FoodBAT could facilitate pharmacological and non-pharmacological interventions to improve metabolic health.
The FoodBAT project was structured around four scientific Work Packages, each addressing a key component of the project's overarching aim: to elucidate how food intake and endocrine factors interact to modulate BAT metabolism in humans, and how this is affected by obesity and cold acclimation.
WP1 –Meal-Induced Thermogenesis (MIT) Study
Activities Performed:
• Conducted a clinical trial with 52 participants (28 lean, 24 with obesity).
• Measured energy expenditure using indirect calorimetry and BAT activity using PET/CT imaging with [18F]FDG, [15O]H2O, and [18F]FTHA tracers.
• Participants underwent a standardized mixed-meal testing under thermoneutrality and after mild cold exposure.
• Serial blood sampling was performed to quantify gut and metabolic hormone levels (such as secretin, GLP-1, GIP, CCK, insulin, thyroid hormones).
• Neck BAT and WAT biopsies were collected.
Main Scientific Outcomes:
• The analysis of the data is ongoing.
• Preliminary findings suggest that acute cold exposure modulates the fasting and postprandial secretion of hormones and is affected by obesity.
WP2 – Cold Acclimation Protocol in volunteers with obesity
Activities Performed:
• Eleven out of 14 individuals finished the study protocol. Volunteers with obesity completed a 3-month cold acclimation protocol (twice-weekly 18°C water immersion).
• Pre- and post-intervention testing included the same PET/CT and MIT protocols as WP1.
Main Scientific Outcomes:
• The analyses are ongoing, but preliminary findings suggest only modest improvements in metabolic outcomes after the intervention.
• Changes in appetite hormones after the intervention were not significant.
WP3 – Gut–BAT-brain Axis study
Activities Performed:
• Carried out a proof-of-concept trial with 13 participants (ongoing study).
• Investigated the relationship between postprandial hormonal responses and BAT metabolism using PET/CT and indirect calorimetry.
• Explored the gut-BAT-brain axis by combining imaging analysis and serial postprandial blood markers.
Main Scientific Outcomes:
• No results are available because the study is in the data collection phase.
WP4 – In Vitro Mechanistic Studies on Human Brown Adipocytes
Activities Performed:
• WAT and BAT samples were collected from volunteers enrolled in WP1 and WP2.
• The group has established human primary brown adipose spheroids.
• Ongoing and planned analyses include gene expression, mitochondrial function, lipolysis, immune profiling, and secretory proteome studies to investigate molecular mechanisms regulating thermogenesis under various stimuli.
Main Scientific Outcomes:
The primary outcome of the research group was successfully developing and validating the human primary brown adipose spheroids. This enables advanced functional and molecular analyses of human BAT. We are currently validating the model, which will be used for various experimental applications.
WP1 –Meal-Induced Thermogenesis (MIT) Study
Activities Performed:
• Conducted a clinical trial with 52 participants (28 lean, 24 with obesity).
• Measured energy expenditure using indirect calorimetry and BAT activity using PET/CT imaging with [18F]FDG, [15O]H2O, and [18F]FTHA tracers.
• Participants underwent a standardized mixed-meal testing under thermoneutrality and after mild cold exposure.
• Serial blood sampling was performed to quantify gut and metabolic hormone levels (such as secretin, GLP-1, GIP, CCK, insulin, thyroid hormones).
• Neck BAT and WAT biopsies were collected.
Main Scientific Outcomes:
• The analysis of the data is ongoing.
• Preliminary findings suggest that acute cold exposure modulates the fasting and postprandial secretion of hormones and is affected by obesity.
WP2 – Cold Acclimation Protocol in volunteers with obesity
Activities Performed:
• Eleven out of 14 individuals finished the study protocol. Volunteers with obesity completed a 3-month cold acclimation protocol (twice-weekly 18°C water immersion).
• Pre- and post-intervention testing included the same PET/CT and MIT protocols as WP1.
Main Scientific Outcomes:
• The analyses are ongoing, but preliminary findings suggest only modest improvements in metabolic outcomes after the intervention.
• Changes in appetite hormones after the intervention were not significant.
WP3 – Gut–BAT-brain Axis study
Activities Performed:
• Carried out a proof-of-concept trial with 13 participants (ongoing study).
• Investigated the relationship between postprandial hormonal responses and BAT metabolism using PET/CT and indirect calorimetry.
• Explored the gut-BAT-brain axis by combining imaging analysis and serial postprandial blood markers.
Main Scientific Outcomes:
• No results are available because the study is in the data collection phase.
WP4 – In Vitro Mechanistic Studies on Human Brown Adipocytes
Activities Performed:
• WAT and BAT samples were collected from volunteers enrolled in WP1 and WP2.
• The group has established human primary brown adipose spheroids.
• Ongoing and planned analyses include gene expression, mitochondrial function, lipolysis, immune profiling, and secretory proteome studies to investigate molecular mechanisms regulating thermogenesis under various stimuli.
Main Scientific Outcomes:
The primary outcome of the research group was successfully developing and validating the human primary brown adipose spheroids. This enables advanced functional and molecular analyses of human BAT. We are currently validating the model, which will be used for various experimental applications.
Overall Project Achievements
The project's main innovation outputs include the development of integrated clinical protocols that investigate how food intake and cold exposure affect the gut–brain–BAT axis, thermogenesis, appetite, and brain activity. These protocols provide new translational tools for future anti-obesity strategies.
Results beyond the state-of-the-art
The project achieved significant scientific and technical progress through the successful implementation of two clinical trials (MOTORBAT and FoodBAT), which combined state-of-the-art PET/CT imaging, indirect calorimetry, and hormonal profiling to investigate the gut–BAT-brain axis in lean individuals and volunteers with obesity.
These studies generated high-quality data on how acute food intake and cold exposure influence BAT metabolism and appetite regulation, providing new insights into inter-individual variability in BAT function.
The FoodBAT study represents a novel approach to understanding the role of acute food intake in controlling energy homeostasis. These outcomes contribute to the state of the art in human metabolic research and offer new translational frameworks to inform obesity prevention and treatment strategies.
The project's main innovation outputs include the development of integrated clinical protocols that investigate how food intake and cold exposure affect the gut–brain–BAT axis, thermogenesis, appetite, and brain activity. These protocols provide new translational tools for future anti-obesity strategies.
Results beyond the state-of-the-art
The project achieved significant scientific and technical progress through the successful implementation of two clinical trials (MOTORBAT and FoodBAT), which combined state-of-the-art PET/CT imaging, indirect calorimetry, and hormonal profiling to investigate the gut–BAT-brain axis in lean individuals and volunteers with obesity.
These studies generated high-quality data on how acute food intake and cold exposure influence BAT metabolism and appetite regulation, providing new insights into inter-individual variability in BAT function.
The FoodBAT study represents a novel approach to understanding the role of acute food intake in controlling energy homeostasis. These outcomes contribute to the state of the art in human metabolic research and offer new translational frameworks to inform obesity prevention and treatment strategies.