High-fat Overfeeding, Hepatokines and Appetite Regulation

Obesity Clinical Trial

— OVEREAT  

Official title:

Influence of High-fat Overfeeding on Circulating Hepatokine Concentrations: a Randomised Crossover Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03369145
• Other study ID #: R17-P144
• Status: Completed
• Phase: N/A
• Start date: December 11, 2017
• Est. completion date: July 31, 2018

Study information

• Verified date: February 2019
• Source: Loughborough University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The present study will investigate the effect of high-fat overfeeding on a group of liver-secreted proteins linked to worsened blood sugar control, as well as proteins involved in appetite control. Participants will consume both a high-fat diet, consisting of 50% extra calories above their daily required intake, and a control diet, consisting of their normal 'habitual' diet, with each diet lasting seven days. The diets will be undertaken in a randomised order, with a period of three weeks separating the two diets. Blood samples will be taken before and after each diet to measure blood sugar control. Further blood samples will also be taken 24 hours and 72 hours into each diet to see how levels of the liver and appetite-regulating proteins change over the course of the seven days.

It is expected that blood sugar control will be worsened by the high-fat diet and this will be accompanied by increases in levels of the liver-secreted proteins and an impaired release of the appetite-regulating proteins into the blood.

Description:

In recent years, researchers have identified a number of liver-secreted proteins, termed "hepatokines", which are thought to play an important role in inter-organ crosstalk between the liver and other metabolically active tissues such as skeletal muscle and adipose tissue. Specifically, previous studies have demonstrated that hepatokines contribute to whole body glucose and lipid homeostasis through acting in an endocrine-like fashion. Understanding how circulating concentrations of these hepatokines can be manipulated in humans is essential, as impaired blood glucose and lipid control is a key feature of metabolic diseases, such as type 2 diabetes and non-alcoholic fatty liver disease.

Previous research at Loughborough University has found that acute high-fat overfeeding for up to seven days can impair glycaemic control; however, the exact mechanisms responsible for these detrimental changes are not fully understood. Based upon previous evidence that hepatokine production is nutritionally modulated, the investigators believe that changes in hepatokine production may play a role in the detrimental metabolic effects seen following short-term, high-fat overfeeding which has implications for long-term metabolic health.

Appetite regulation is also thought to play a role in the pathophysiology of obesity and insulin resistance, as the impaired secretion of several appetite regulatory hormones in both fasting and postprandial conditions has been observed in obesity, which is characterised by an chronic excessive energy intake. Therefore, the investigators are also interested to examine the appetite regulatory hormone response to short-term, high-fat overfeeding.

The present study is a randomised, controlled, crossover study in which twelve recreationally active, healthy males will consume both a hypercaloric, high-fat diet (consisting of 50% extra energy above the daily requirement, 65% of which is fat) and a control diet (the participants' habitual diet) in a randomised fashion. A three-week washout period will separate the two diets in order to remove any lasting effects confounding the subsequent diet.

Following a prescreening session in which anthropometric data will be collected, participants will commence their first dietary condition. An oral glucose tolerance test will be performed before and after the two diets to measure changes in glycaemic control/whole body insulin sensitivity. Further blood samples will be taken 24 hours and 72 hours after commencing the diets in order to observe the time course of any changes in circulating hepatokine and appetite hormone concentrations. Physical activity will also be monitored for the duration of the two dietary conditions to ensure that habitual physical activity levels are maintained.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: July 31, 2018
• Est. primary completion date: July 31, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Recreationally active - = 2 structured exercise sessions per week

• BMI between 18.5 - 27.9 kg/m2

• Body fat percentage < 20%

• Metabolically healthy - No known cardiovascular or metabolic disease such as diabetes, respiratory or heart disease.

• Non-smoker

• Weight stable in the past 6 months

• Normal fasting blood glucose levels (3.6 - 5.5 mmol/l)

Exclusion Criteria:

• Contraindications to exercise

• Needle Phobia

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Fatty Liver
• Insulin Resistance
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease
• Obesity
• Type2 Diabetes Mellitus

Intervention

Dietary Supplement:
• High-fat diet
The high-fat diet will provide 7 days of overfeeding comprising of: +50% extra calories above the daily required intake, 65% of which is fat.

Locations

Country	Name	City	State
United Kingdom	National Centre for Sport and Exercise Medicine, Loughborough University	Loughborough	Leicestershire
United Kingdom	Clifton Campus, Nottingham Trent University	Nottingham	Nottinghamshire

Sponsors (3)

Lead Sponsor	Collaborator
Loughborough University	Nottingham Trent University, Nottingham University Hospitals NHS Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (9)

Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007 Jun;5(6):426-37. — View Citation

Dasgupta S, Bhattacharya S, Biswas A, Majumdar SS, Mukhopadhyay S, Ray S, Bhattacharya S. NF-kappaB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance. Biochem J. 2010 Aug 1;429(3):451-62. doi: 10.1042/BJ20100330. — View Citation

Groop LC. Insulin resistance: the fundamental trigger of type 2 diabetes. Diabetes Obes Metab. 1999 May;1 Suppl 1:S1-7. Review. — View Citation

Hulston CJ, Churnside AA, Venables MC. Probiotic supplementation prevents high-fat, overfeeding-induced insulin resistance in human subjects. Br J Nutr. 2015 Feb 28;113(4):596-602. doi: 10.1017/S0007114514004097. Epub 2015 Jan 29. — View Citation

Lan F, Misu H, Chikamoto K, Takayama H, Kikuchi A, Mohri K, Takata N, Hayashi H, Matsuzawa-Nagata N, Takeshita Y, Noda H, Matsumoto Y, Ota T, Nagano T, Nakagen M, Miyamoto K, Takatsuki K, Seo T, Iwayama K, Tokuyama K, Matsugo S, Tang H, Saito Y, Yamagoe S, Kaneko S, Takamura T. LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes. 2014 May;63(5):1649-64. doi: 10.2337/db13-0728. Epub 2014 Jan 29. — View Citation

Lean ME, Malkova D. Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence? Int J Obes (Lond). 2016 Apr;40(4):622-32. doi: 10.1038/ijo.2015.220. Epub 2015 Oct 26. Review. — View Citation

Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017 Sep;13(9):509-520. doi: 10.1038/nrendo.2017.56. Epub 2017 Jun 9. Review. — View Citation

Parry SA, Smith JR, Corbett TR, Woods RM, Hulston CJ. Short-term, high-fat overfeeding impairs glycaemic control but does not alter gut hormone responses to a mixed meal tolerance test in healthy, normal-weight individuals. Br J Nutr. 2017 Jan;117(1):48-55. doi: 10.1017/S0007114516004475. Epub 2017 Jan 24. Erratum in: Br J Nutr. 2017 Feb;117(4):622. — View Citation

Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H, Arai H, Takei Y, Masuda M, Tanimura A, Harada N, Yamanaka-Okumura H, Takeda E. Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor? PLoS One. 2011;6(8):e22976. doi: 10.1371/journal.pone.0022976. Epub 2011 Aug 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Leukocyte cell-derived chemotaxin 2 (LECT2)	Time-course of LECT2 plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	Fibroblast growth factor 21 (FGF21)	Time-course of FGF21 plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	Fetuin-A	Time-course of Fetuin-A plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	Acylated ghrelin	Time-course of acylated ghrelin plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	Peptide YY (PYY)	Time-course of PYY plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	C-Terminal Telopeptide of Type 1 Collagen (CTX)	Time-course of CTX plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	N-Terminal Propeptide of Type 1 Procollagen (P1NP)	Time-course of P1NP plasma concentrations across the 7-day dietary interventions	Baseline, 1 day, 3 days, 7 days
Secondary	Visual Analogue Scale for Subjective Ratings of Appetite	Time-course of subjective ratings of hunger across the 7-day dietary interventions, measured using an appetite visual analogue scale. The scale is divided into subscales of different appetite perceptions including: hunger, fullness, satisfaction and prospective food consumption. Each subscale is rated on a 100mm scale (i.e. from 0 - 100), with a rating of 100 fully supporting the perception and a rating of 0 fully opposing the perception.	Baseline, 1 day, 3 days, 7 days
Secondary	Subjective food preference	Time-course of subjective food preference across the 7-day dietary interventions, measured using the Leeds Food Preference Questionnaire.	Baseline, 1 day, 3 days, 7 days
Secondary	Whole-body insulin sensitivity	Changes in whole-body insulin sensitivity using the Matsuda Index, calculated from plasma glucose and insulin concentrations during the oral glucose tolerance test	Baseline, 7 Days
Secondary	Homeostasis model assessment of insulin resistance (HOMA-IR)	Changes in HOMA-IR (a marker of hepatic insulin resistance) using baseline concentrations of plasma glucose and insulin.	Baseline, 1 day, 3 days, 7 days
Secondary	Adipose tissue insulin resistance (ADIPO-IR)	Changes in ADIPO-IR using baseline concentrations of plasma insulin and non-esterified free fatty acids.	Baseline, 1 day, 3 days, 7 days
Secondary	Physical activity and sedentary behaviour	Amounts of sitting time, standing time, light activity and moderate-vigorous activity will be measured across the duration of each diets to compare between the two. This will be Measured using Acitgraph and ActivPAL monitors.	7 days (per diet)
Secondary	Resting Metabolic Rate	Changes in resting metabolic rate in response to the diets will be measured using indirect calorimetry and estimated using the Haldane transformation.	Baseline, 7 Days
Secondary	Fat Oxidation	Changes in fat oxidation in response to the diets will be measured using indirect calorimetry and estimated using the Haldane transformation.	Baseline, 7 Days
Secondary	Blood pressure	Changes in blood pressure (systolic and diastolic) across the two dietary interventions will be measured using an automated pressure cuff.	Baseline, 1 day, 3 days, 7 days
Secondary	Body weight	Changes in body weight across the two dietary interventions.	Baseline, 1 day, 3 days, 7 days
Secondary	Body fat percentage	Changes in body fat percentage across the two dietary interventions using bioelectrical impedance analysis.	Baseline, 7 Days