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Brain function and glucocorticoids in obesity and type 2 diabetes including effects of lifestyle interventions
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.ORCID iD: 0000-0002-9169-1059
2015 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Effekter av livsstilsförändring på hjärnfunktion och stresshormoner vid fetma och typ 2 diabetes (Swedish)
Abstract [en]

Background Obesity and associated metabolic dysregulation are linked to impaired cognitive function and alterations in brain structure, which increases the risk of age-related dementia. Increased glucocorticoid (GC) exposure may be a potential mediator of these negative effects on the brain.

Methods and results In paper 1, we tested the relationship between cortisol levels, brain morphology and cognitive function in 200 women and men. Salivary cortisol levels were negatively related to cortical surface areas in prefrontal brain regions in both sexes. In participants with type 2 diabetes, high salivary cortisol levels were associated with lower memory performance. In paper 2, we tested in 70 overweight women the effects on tissue-specific GC metabolism of a Paleolithic diet or a diet following the Nordic nutrition recommendations. The 24-month interventions led to decreased expression of the GC-activating enzyme 11βHSD1 in adipose tissue, interpreted as a normalization of an obesity-related disturbance in GC metabolism. Furthermore, GC metabolism by 5α-reductase increased substantially after 2 years, an unexpected and novel result. The outcomes did not differ by diet. In paper 3, 20 women included in paper 2 were examined with functional magnetic resonance imaging (fMRI) while performing a memory task at baseline and after 6 months. Memory performance improved and functional brain responses increased in the hippocampus. Once again, the results were similar in both diet groups. In paper 4, 24 overweight participants with type 2 diabetes were examined with fMRI, using the same memory test as in paper 3, at baseline and after 12 weeks of intervention with a Paleolithic diet with or without exercise training. Functional brain response increased in the hippocampus, but memory was not improved. The addition of physical exercise did not alter the results.

Conclusion Cortisol levels are linked to prefrontal brain structure and, at least in type 2 diabetes, lower memory performance. Furthermore, the dysregulated GC metabolism in obesity can be reversed by long-term diet- induced weight loss. Finally, dietary interventions with associated metabolic improvements alter functional brain responses during memory testing, including increased activation of the hippocampus. Whether these changes are linked to alterations in GC exposure and mediate improved cognition requires further study. 

Place, publisher, year, edition, pages
Umeå: Umeå University , 2015. , 85 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1710
Keyword [en]
Obesity, type 2 diabetes, glucocorticoid, cortisol, 11beta hydroxysteroid dehydrogenase type 1, episodic memory, functional magnetic resonance imaging, paleolithic diet, exercise
National Category
Endocrinology and Diabetes Neurosciences
Research subject
Internal Medicine; Medicine
Identifiers
URN: urn:nbn:se:umu:diva-102596ISBN: 978-91-7601-250-5 (print)OAI: oai:DiVA.org:umu-102596DiVA: diva2:808457
Public defence
2015-05-27, Bergasalen, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2015-05-06 Created: 2015-04-28 Last updated: 2016-05-27Bibliographically approved
List of papers
1. Higher diurnal salivary cortisol levels are related to smaller prefrontal cortex surface area in women and men
Open this publication in new window or tab >>Higher diurnal salivary cortisol levels are related to smaller prefrontal cortex surface area in women and men
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(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-102593 (URN)
Available from: 2015-04-28 Created: 2015-04-28 Last updated: 2015-12-07
2. Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women
Open this publication in new window or tab >>Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women
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2015 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 39, no 5, 814-819 p.Article in journal (Refereed) Published
Abstract [en]

Background/Objectives: Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women.

Subjects/Methods: Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue were studied.

Results: Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11βHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11βHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months.

Conclusions: Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-96782 (URN)10.1038/ijo.2014.188 (DOI)000354097900013 ()25349058 (PubMedID)
Available from: 2014-12-03 Created: 2014-12-03 Last updated: 2017-12-05Bibliographically approved
3. Diet-Induced Weight Loss alters Functional Brain Responses during an Episodic Memory Task
Open this publication in new window or tab >>Diet-Induced Weight Loss alters Functional Brain Responses during an Episodic Memory Task
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2015 (English)In: Obesity Facts, ISSN 1662-4025, E-ISSN 1662-4033, Vol. 8, 261-272 p.Article in journal (Refereed) Published
Abstract [en]

Objective: It has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women. Methods: 20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 months. We used functional magnetic resonance imaging to examine brain function during an episodic memory task as well as anthropometric and biochemical data before and after the interventions. Results: Episodic memory performance improved significantly (p = 0.010) after the dietary interventions. Concomitantly, brain activity increased in the anterior part of the right hippocampus during memory encoding, without differences between diets. This was associated with decreased levels of plasma free fatty acids (FFA). Brain activity increased in pre-frontal cortex and superior/middle temporal gyri. The magnitude of increase correlated with waist circumference reduction. During episodic retrieval, brain activity decreased in inferior and middle frontal gyri, and increased in middle/superior temporal gyri. Conclusions: Diet-induced weight loss, associated with decreased levels of plasma FFA, improves episodic memory linked to increased hippocampal activity.

Keyword
Functional magnetic resonance imaging, Episodic memory, Obesity, Diet interventions, Hippocampus
National Category
Neurosciences Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-101039 (URN)10.1159/000437157 (DOI)000360933400004 ()26139105 (PubMedID)
Available from: 2015-03-18 Created: 2015-03-18 Last updated: 2017-12-04Bibliographically approved
4. A Paleolithic diet alters functional brain responses during an episodic memory task in type 2 diabetes
Open this publication in new window or tab >>A Paleolithic diet alters functional brain responses during an episodic memory task in type 2 diabetes
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(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-102594 (URN)
Available from: 2015-04-28 Created: 2015-04-28 Last updated: 2015-05-04

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