Clinical trial NCT04482738: Study of the Effects of Overfeeding on Glucocorticoids in Lean and Obese Subjects
Official title: The Acute Response of Glucocorticoids Upon Food Intake
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Overweight and Obesity
Keywords: obesity
overweight
cortisol
overfeeding
glucocorticoids
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2020-07-22
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Community sample. The obese group will be both a community and a clinical sample.

Brief summary: Investigators suggest that in lean subjects cortisol increases in response to overfeeding and that this increase is blunted in obese subjects. A group of 18 male healthy lean subjects and another group of 18 male healthy obese subjects will undergo a high-calorie meal test. Prior to the meal intake, an indirect calorimetry, bioelectrical impedance, heart rate variability, a fasting blood sample and a perceived stress questionnaire will be assessed. After intake of the study meal, blood tests will be performed in order to measure the secretion of cortisol, glucose and lipid metabolism and inflammatory markers. Indirect calorimetry will be assessed again 60 and 180 minutes after the meal intake.

Detailed description: Obesity is one of the most serious health problems in the 21st century. High energy food and a sedentary lifestyle are driving the current obesity pandemic. These factors activate the hypothalamic-pituitary-adrenal (HPA) axis, the key regulatory pathway of energy homeostasis. Activation of the HPA-axis leads to secretion of glucocorticoids from the adrenal glands, which control energy homeostasis by mobilizing and redistributing energy substrates.

Animal models of obesity have shown that glucocorticoids play a key role in the development of the metabolic syndrome. However, studies in humans yielded conflicting results. These studies have a major limitation in common. They do not consider glucocorticoid rhythmicity but rather investigate a snapshot of glucocorticoid secretion. Rhythmicity, however, is crucial because already minor glucocorticoid phase disturbances cause disease and could contribute to obesity.

Interestingly, excessive food intake may increase cortisol levels in healthy subjects . The consequence of this food-induced cortisol peak is not understood, but it may be key to restoring energy homeostasis after a meal. Whether the food-induced cortisol peak in obese subjects is disturbed is not known

With this study, investigators aim to better understand the role played by glucocorticoids in the origin of overweight and obesity. Researchers will investigate, in lean and obese subjects, whether the pulsatile release of cortisol increases after intake of a high-calorie meal. 36 subjects will take part in the study: a group of 18 male lean subjects and a second group of 18 male obese patients.

Eligibility criteria: Inclusion Criteria:

* Body mass index (BMI) \>18,5 and \<25 kg/m2
* BMI \>30 kg/m2

Exclusion Criteria:

* Any clinically significant concomitant diseases in lean subjects
* Any clinically significant concomitant diseases in obese subjects apart from features of the metabolic syndrome (dyslipidemia, arterial hypertension and insulin resistance)
* Lactose intolerance
* Severe food allergy
* Regular alcohol consumption (\>30 g/d)
* Regular fitness training (\>4 hours/week)
* Previous enrolment in a clinical trial within the last 3 months
* Inability or contradictions to undergo the investigated intervention
* Inability to follow the procedures of the study

Primary outcomes:
measure: Change in pulsatile secretion of cortisol in response to a high-calorie meal (nmol/l)
timeFrame: 195 minutes
Secondary outcomes:
measure: Thyroid hormones (nmol/l)
timeFrame: 195 minutes
measure: Growth Hormone (mIU/l)
timeFrame: 195 minutes
measure: Catecholamines (pg/ml)
timeFrame: 195 minutes
measure: Adrenocorticotropic Hormone (ACTH) (pg/ml)
timeFrame: 195 minutes
measure: Glucagon-like-peptide-1 (GLP-1) (pg/ml)
timeFrame: 195 minutes
measure: Gastric inhibitory polypeptide (GIP) (pg/ml)
timeFrame: 195 minutes
measure: Peptide YY (PYY) (pg/ml)
timeFrame: 195 minutes
measure: Glucose (mmol/l)
timeFrame: 195 minutes
measure: Insulin (mIU/l)
timeFrame: 195 minutes
measure: C-Peptide (pmol/l)
timeFrame: 195 minutes
measure: Total cholesterol (mmol/l)
timeFrame: 195 minutes
measure: Low density lipoprotein (LDL)-cholesterol (mmol/l)
timeFrame: 195 minutes
measure: High density lipoprotein (HDL)-cholesterol (mmol/l)
timeFrame: 195 minutes
measure: Triglycerides (mmol/l)
timeFrame: 195 minutes
measure: Growth differentiation factor 15 (GDF15) (ng/l)
timeFrame: 195 minutes
measure: High-sensitive c-reactive Protein (hsCRP) (mg/l)
timeFrame: 195 minutes
measure: Interleukin-6 (IL-6) (pg/ml)
timeFrame: 195 minutes
measure: Interleukin-8 (IL-8) (pg/ml)
timeFrame: 195 minutes
measure: Interleukin-1 receptor Antagonist (IL-1Ra) (pg/ml)
timeFrame: 195 minutes
measure: Heart rate (bpm)
timeFrame: 5 minutes
measure: Blood pressure: diastolic and systolic blood pressure (mmHg)
timeFrame: 1 minute
measure: Weight: kilogram body weight (kg)
timeFrame: 1 minute
measure: Energy expenditure: basal metabolic rate
timeFrame: 200 minutes
measure: Substrate utilisation: respiratory quotient
timeFrame: 200 minutes
measure: Fat and lean mass (kg)
timeFrame: 20 minutes
measure: Total body water (l)
timeFrame: 20 minutes
measure: Appetite: visual analogue scale rating
timeFrame: 3 hours
measure: Stress: perceived stress Levels (0-56)
timeFrame: 5 minutes
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel
state: Basel-Stadt
Study officials:
affiliation: University Hospital, Basel, Switzerland
name: Eleonora Seelig, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prospective Studies Collaboration; Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009 Mar 28;373(9669):1083-96. doi: 10.1016/S0140-6736(09)60318-4. Epub 2009 Mar 18.
citation: van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015 Mar 26;161(1):119-132. doi: 10.1016/j.cell.2015.03.008.
citation: Vgontzas AN, Lin HM, Papaliaga M, Calhoun S, Vela-Bueno A, Chrousos GP, Bixler EO. Short sleep duration and obesity: the role of emotional stress and sleep disturbances. Int J Obes (Lond). 2008 May;32(5):801-9. doi: 10.1038/ijo.2008.4. Epub 2008 Feb 5.
citation: de Guia RM, Rose AJ, Herzig S. Glucocorticoid hormones and energy homeostasis. Horm Mol Biol Clin Investig. 2014 Aug;19(2):117-28. doi: 10.1515/hmbci-2014-0021.
citation: Russell G, Lightman S. The human stress response. Nat Rev Endocrinol. 2019 Sep;15(9):525-534. doi: 10.1038/s41574-019-0228-0. Epub 2019 Jun 27.
citation: Ferrau F, Korbonits M. Metabolic Syndrome in Cushing's Syndrome Patients. Front Horm Res. 2018;49:85-103. doi: 10.1159/000486002. Epub 2018 Apr 5.
citation: Livingstone DE, Grassick SL, Currie GL, Walker BR, Andrew R. Dysregulation of glucocorticoid metabolism in murine obesity: comparable effects of leptin resistance and deficiency. J Endocrinol. 2009 May;201(2):211-8. doi: 10.1677/JOE-09-0003. Epub 2009 Feb 17.
citation: Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology. 2000 Feb;141(2):560-3. doi: 10.1210/endo.141.2.7297.
citation: Liu Y, Nakagawa Y, Wang Y, Li R, Li X, Ohzeki T, Friedman TC. Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes. 2003 Jun;52(6):1409-16. doi: 10.2337/diabetes.52.6.1409.
citation: Chalew S, Nagel H, Shore S. The hypothalamic-pituitary-adrenal axis in obesity. Obes Res. 1995 Jul;3(4):371-82. doi: 10.1002/j.1550-8528.1995.tb00163.x.
citation: Marin P, Darin N, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism. 1992 Aug;41(8):882-6. doi: 10.1016/0026-0495(92)90171-6.
citation: Duclos M, Corcuff JB, Etcheverry N, Rashedi M, Tabarin A, Roger P. Abdominal obesity increases overnight cortisol excretion. J Endocrinol Invest. 1999 Jun;22(6):465-71. doi: 10.1007/BF03343591.
citation: Pasquali R, Cantobelli S, Casimirri F, Capelli M, Bortoluzzi L, Flamia R, Labate AM, Barbara L. The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab. 1993 Aug;77(2):341-6. doi: 10.1210/jcem.77.2.8393881.
citation: Chalew SA, Lozano RA, Armour KM, Zadik Z, Kowarski AA. Reduction of plasma cortisol levels in childhood obesity. J Pediatr. 1991 Nov;119(5):778-80. doi: 10.1016/s0022-3476(05)80302-6. No abstract available.
citation: Chalew SA, Nagel H, Burt D, Edwards CR. The integrated concentration of cortisone is reduced in obese children. J Pediatr Endocrinol Metab. 1997 May-Jun;10(3):287-90. doi: 10.1515/JPEM.1997.10.3.287.
citation: Jessop DS, Dallman MF, Fleming D, Lightman SL. Resistance to glucocorticoid feedback in obesity. J Clin Endocrinol Metab. 2001 Sep;86(9):4109-14. doi: 10.1210/jcem.86.9.7826.
citation: Strain GW, Zumoff B, Strain JJ, Levin J, Fukushima DK. Cortisol production in obesity. Metabolism. 1980 Oct;29(10):980-5. doi: 10.1016/0026-0495(80)90043-8.
citation: Pasquali R, Anconetani B, Chattat R, Biscotti M, Spinucci G, Casimirri F, Vicennati V, Carcello A, Labate AM. Hypothalamic-pituitary-adrenal axis activity and its relationship to the autonomic nervous system in women with visceral and subcutaneous obesity: effects of the corticotropin-releasing factor/arginine-vasopressin test and of stress. Metabolism. 1996 Mar;45(3):351-6. doi: 10.1016/s0026-0495(96)90290-5.
citation: Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 1998 Jun;83(6):1853-9. doi: 10.1210/jcem.83.6.4843.
citation: Longui CA, Giusti MM, Calliari LE, Katiki T, Kochi C, Monte O. Partial glucocorticoid resistance in obese children detected by very low dose dexamethasone suppression test. J Pediatr Endocrinol Metab. 2003 Dec;16(9):1277-82. doi: 10.1515/jpem.2003.16.9.1277.
citation: Ljung T, Andersson B, Bengtsson BA, Bjorntorp P, Marin P. Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a dose-response study. Obes Res. 1996 May;4(3):277-82. doi: 10.1002/j.1550-8528.1996.tb00546.x.
citation: Woods C, Tomlinson JW. The Dehydrogenase Hypothesis. Adv Exp Med Biol. 2015;872:353-80. doi: 10.1007/978-1-4939-2895-8_16.
citation: van Rossum EF. Obesity and cortisol: New perspectives on an old theme. Obesity (Silver Spring). 2017 Mar;25(3):500-501. doi: 10.1002/oby.21774. No abstract available.
citation: Al-Damluji S, Iveson T, Thomas JM, Pendlebury DJ, Rees LH, Besser GM. Food-induced cortisol secretion is mediated by central alpha-1 adrenoceptor modulation of pituitary ACTH secretion. Clin Endocrinol (Oxf). 1987 May;26(5):629-36. doi: 10.1111/j.1365-2265.1987.tb00819.x.
citation: Benedict C, Hallschmid M, Scheibner J, Niemeyer D, Schultes B, Merl V, Fehm HL, Born J, Kern W. Gut protein uptake and mechanisms of meal-induced cortisol release. J Clin Endocrinol Metab. 2005 Mar;90(3):1692-6. doi: 10.1210/jc.2004-1792. Epub 2004 Dec 7.
citation: Follenius M, Brandenberger G, Hietter B. Diurnal cortisol peaks and their relationships to meals. J Clin Endocrinol Metab. 1982 Oct;55(4):757-61. doi: 10.1210/jcem-55-4-757.
citation: Ibrahim M, Bonfiglio S, Schlogl M, Vinales KL, Piaggi P, Venti C, Walter M, Krakoff J, Thearle MS. Energy Expenditure and Hormone Responses in Humans After Overeating High-Fructose Corn Syrup Versus Whole-Wheat Foods. Obesity (Silver Spring). 2018 Jan;26(1):141-149. doi: 10.1002/oby.22068. Epub 2017 Nov 28.
citation: GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12.