Dietary Temperature’s Influence on Energy Balance in Humans: Protocol for a Randomized Controlled Trial and Crossover Design

JMIR Research Protocols · 2 authors, 2 centres

AI SUMMARY

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POPULATIONHealthy adults (BMI 25-35 kg/m²), aged 19-65 years, not currently dieting, no weight change >2 kg in past 3 months, no medications affecting energy expenditure, non-smokers, not pregnant/lactating

INTERVENTIONDiets served at graded temperatures: 42°C, 47°C, and 52°C (5°C increments above core body temperature)

COMPARISONThermoneutral diet served at 37°C

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TL;DR

This paper proposes a novel hypothesis that the temperature of ingested food and beverages may influence energy balance and contribute to obesity through the expression of heat shock proteins (HSPs), particularly HSP-70 and HSP-90. The authors present a detailed protocol for a 4-arm randomized controlled trial and crossover design to test whether meals served at different temperatures (37°C to 52°C) affect body weight, adiposity, and metabolic markers over 12 weeks. If confirmed, dietary temperature would need to be controlled for in future metabolic and obesity research, potentially revising prior study conclusions.

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**Background:** The authors challenge the conventional assumption that thermal energy from food is dissipated during digestion and does not contribute to energy balance. They propose that dietary temperature influences energy homeostasis through heat shock proteins (HSPs), especially HSP-70 and HSP-90, which possess N-terminal ATPase fragments that regulate ATP activity and hydrolysis. Obesity has been linked to increased HSP expression: serum HSP-27, HSP-60, HSP-65, HSP-70, and HSP-72 antibody levels are significantly elevated in people with obesity compared to normal-weight controls. In diet-induced obese mouse models, HSP-90 inhibitors improve glucose regulation, and HSP-90β knockdown reverses insulin resistance. The authors cite evidence that both intracellular and extracellular HSP-70 levels are significantly greater in participants with obesity than lean controls, and that the ratio of extracellular to intracellular HSP-70 may trigger chronic proinflammatory status leading to insulin resistance and type 2 diabetes. A prior RCT by Roumans et al (2016) found that weight regainers showed increased expression of calnexin, β-actin, HSP-27, HSP-60, and HSP-70. Another RCT in 20 young overweight men found reduced expression of HSP-90 and HSP-27 after a 3-week low-fat diet and exercise program. Animal studies in pigs show that heat stress (41.5°C) enhances adipocyte triglyceride storage through upregulation of genes involved in fatty acid uptake and triglyceride synthesis, with significantly greater cellular ATP under heat stress versus control temperature.

**Methods:** The authors propose a 4-arm randomized controlled trial with 80 healthy participants (BMI 25-35 kg/m², aged 19-65 years) randomized 1:1:1:1 to receive diets served at 37°C (thermoneutral), 42°C, 47°C, or 52°C for 12 weeks. Participants will consume boluses of soups (100 mL each) with energy content matched to individually calculated energy demands (20% breakfast, 50% lunch, 30% dinner). The day before experimental sessions, participants will avoid alcohol, caffeine, and strenuous exercise. Measurements will occur in a whole-body calorimeter at 35°C with ~20% relative humidity. Blood samples will be collected after 12-hour fasting at 0, 6, and 12 weeks. Adipose tissue biopsies and in vitro cell culture experiments will be performed. Primary outcomes include changes in BMI, body fat, body weight, waist-hip ratio, HSP levels (HSP-27, HSP-65, HSP-70, HSP-72, HSP-90) and their antibodies, and metabolic markers (motilin, fasting glucose, insulin, C-peptide, 2-hour glucose, HOMA-IR). Secondary outcomes include total cholesterol, triglycerides, LDL, HDL, reactive oxygen species, reactive nitrogen species, and NF-κB. A crossover design with 2-week washout periods is also proposed. Sample size calculations are based on the R value (eHSP-70 to iHSP-70 ratio), with 80 participants needed (20 per arm) to achieve adequate power.

**Key Results:** This is a protocol paper only; no trial has been initiated and funding has not been sought at the time of publication. No results are available.

**Clinical Implications:** If dietary temperature proves to influence energy balance through HSP-mediated mechanisms, this would have profound implications for metabolic research. Future clinical trials would need to control for dietary temperature when analyzing data. Published metabolic studies may need to be revisited. Dietary recommendations for daily energy intake across age groups and disease states would require adjustment. Cross-cultural comparisons of dietary patterns and obesity rates would need to account for differences in customary food and beverage temperatures. The authors also suggest that dietary temperature may confound the relationship between self-reported energy intake and actual energy balance, potentially explaining discrepancies in studies using dietary assessment tools.

PICO

PPOPULATION

Healthy adults (BMI 25-35 kg/m²), aged 19-65 years, not currently dieting, no weight change >2 kg in past 3 months, no medications affecting energy expenditure, non-smokers, not pregnant/lactating

IINTERVENTION

Diets served at graded temperatures: 42°C, 47°C, and 52°C (5°C increments above core body temperature)

OOUTCOME

Primary: change in BMI, total body fat, body weight, percentage body fat, lean body mass, waist circumference, waist-hip ratio; changes in HSP-27, HSP-65, HSP-70, HSP-72, HSP-90 and their antibodies; changes in motilin, fasting glucose, insulin, C-peptide, 2-hour glucose, HOMA-IR. Secondary: total cholesterol, triglycerides, LDL, HDL, reactive oxygen species, reactive nitrogen species, NF-κB.

STUDY TYPE

other

SPECIALTY

endocrinology

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100% · A

ORIGINAL PAPER

PMC10024216

Dietary Temperature’s Influence on Energy Balance in Humans: Protocol for a Randomized Controlled Trial and Crossover Design

JMIR Research Protocols

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ABSTRACT

Abstract Background According to the first law of thermodynamics, energy cannot be created or destroyed in an isolated system. Water has a characteristically high heat capacity, indicating that the temperature of ingested fluids and meals could contribute to energy homeostasis. Citing the underlying molecular mechanisms, we present a novel hypothesis that states that the temperature of one’s food and drink contributes to energy balance and plays a role in the development of obesity. We provide strong associations with certain molecular mechanisms that are activated by heat and correlate them with obesity and a hypothetical trial that could test this hypothesis. We conclude that if meal or drink temperature proves to contribute to energy homeostasis, then depending on its contribution and scale, future clinical trials should attempt to adjust this effect when analyzing data. In addition, previous research and established relationships of disease states with dietary patterns, energy intake, and food component intakes should be revisited. We understand the common assumption that thermal energy in food is absorbed by the body during digestion and dissipated as heat into the environment, not contributing to the energy balance. We challenge this assumption herein, including a proposed study design that would test our hypothesis. Objective This paper hypothesizes that the temperature of ingested foods or fluids influences energy homeostasis through the expression of heat shock proteins (HSPs), especially HSP-70 and HSP-90, which are expressed to a greater extent in obesity and are known to cause deficits in glucose metabolism. Methods We provide preliminary evidence supporting our hypothesis that greater dietary temperatures disproportionally induce activation of both intracellular and extracellular HSPs and that these HSPs influence energy balance and contribute to obesity. Results This trial protocol has not been initiated and funding has not been sought at the time of this publication. Conclusions To date, no clinical trials are available regarding the potential effects of meal and fluid temperature on weight status or its confounding effects in data analysis. A potential mechanism is proposed as a basis by which higher temperatures of foods and beverages might influence energy balance via HSP expression. On the basis of the evidence supporting our hypothesis, we propose a clinical trial that will further elucidate these mechanisms. International Registered Report Identifier (IRRID) PRR1-10.2196/42846 Keywords: dietary temperature, energy intake, energy conservation, heat shock proteins, clinical trial, design of study

CITATION EXPORT

Reza Rastmanesh, Kyle D Flack. Dietary Temperature’s Influence on Energy Balance in Humans: Protocol for a Randomized Controlled Trial and Crossover Design. JMIR Research Protocols. (2023). https://doi.org/10.2196/42846

AUTHORS

2 · 2 CENTRES

Reza Rastmanesh, Kyle D Flack

1American Physical Society, Maryland, MD, United States
2Department of Dietetics and Human Nutrition, University of Kentucky, Lexington, KY, United States