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While obesity and type 2 diabetes (T2D) are associated with altered dopaminergic activity in the central nervous system and in adipose tissue (AT), the directions and underlying mechanisms remain inconclusive. Therefore, we characterized changes in the abundance of dopamine, its metabolites, and receptors DRD1 and DRD2 in the brain and AT upon dietary intervention or obesity. Male Wistar rats were fed either a standard pellet diet, a cafeteria diet inducing obesity and insulin resistance, or a calorie-restricted diet for 12 weeks. Abundance of dopamine and its receptors DRD1 and DRD2 were examined in brain regions relevant for feeding behavior and energy homeostasis. Furthermore, DRD1 and DRD2 protein levels were analyzed in rat inguinal and epidydimal AT and in human subcutaneous and omental AT from individuals with or without obesity. Rats with diet-induced obesity displayed higher dopamine levels, as well as DRD1 or DRD2 receptor levels in the caudate putamen and the nucleus accumbens core. Surprisingly, caloric restriction induced similar changes in DRD1 and DRD2, but not in dopamine levels, in the brain. Both diets reduced DRD1 abundance in inguinal and epidydimal AT, but upregulated DRD2 levels in inguinal AT. Furthermore, in human obesity, DRD1 protein levels were elevated only in omental AT, while DRD2 was upregulated in both omental and subcutaneous AT. These findings highlight dopaminergic responses to changes in energy balance, occurring both in the brain and AT. We propose that dopaminergic pathways are involved in tissue crosstalk during the development of obesity and T2D.

Obesity is a global health concern associated with increased morbidity and mortality, yet effective treatment strategies are lacking. So far, of all available treatments bariatric surgery has been shown to induce considerable and durable weight loss.

Recent evidence suggests that profound changes are happening in the brain and in the neuroendocrine system after gastric bypass, leading to the question “Is bariatric surgery brain surgery?”. Therefore, investigation into the meaning and significance of these changes is warranted to better depict the role of the brain in mediating the favorable metabolic adaptations induced by bariatric surgery.

This doctoral project aims to cast light on the brain- and hormone-mediated mechanisms that underlie the beneficial metabolic effects of bariatric surgery, and to pave the way to the development of new strategies for the prevention and treatment of obesity and T2D.

We deploy state-of-the-art methods combined, including the hyperinsulinemic glucose clamp, neuroimaging techniques, and hormonal measurements to translationally address the research question. Investigations are performed in the fasting state and under dynamic metabolic challenges, such as intravenous arginine challenge, oral glucose load, or hyperinsulinemic normo- and hypoglycemia, since metabolism is never fully understandable only in the fasting state.

In paper I, we show how gastric bypass alters brain connectivity of several neural pathways involved in reward, inhibitory control, and energy homeostasis during hypoglycemia. In paper II, we explored how gastric bypass is associated with region-specific patterns of changes in glucose uptake in the brain. Paper III shows changes in ACTH, cortisol, GH, and gut hormone levels during the OGTT after gastric bypass in individuals with type 2 diabetes. In paper IV, we report changes in the activity of several hormonal systems during an oral glucose load occurring shortly after bariatric surgery but not after a low-energy diet despite similar weight loss.

Altogether, these results expand the knowledge about the mechanisms underlying the beneficial metabolic effects of bariatric surgery, highlighting the importance of exploring further the role of the brain and neuroendocrine systems, eventually to identify new therapeutic targets against obesity and T2D.

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions.

Purpose

We aimed to characterize the RYGB-induced changes in the dynamics of brain glucose uptake. We addressed heterogeneity between brain regions during experimental normo- and hypoglycemia and explored associations with anthropometric and metabolic outcomes of RYGB.

Methods

Analyses of regional brain glucose uptake were performed on 9 individuals with obesity and no diabetes, investigated with combined brain ¹⁸F-FDG-PET and fMRI during hyperinsulinemic normo- and hypoglycemic clamp, one month before and four months after RYGB. FDG clearance, reflecting glucose uptake rate, was assessed in 38 brain regions, covering all cortical areas and subcortical nuclei, during hyperinsulinemic normo- and hypoglycemia. Correlation analyses were performed to identify associations with other outcomes of RYGB.

Results

FDG uptake rate during hypoglycemia was higher than during normoglycemia in all brain regions, both before and after RYGB. Moreover, in most regions and especially in cortical areas involved in inhibitory behavioral control, FDG uptake rate tended to be reduced after surgery during normoglycemia but elevated during hypoglycemia. However, these post-surgical changes in FDG uptake rate were opposite in the hypothalamus. Thus, the hypo-to-normoglycemia FDG clearance ratio tended to increase in all brain regions following RYGB, but not in the amygdala and the hypothalamus. Changes in regional FDG uptake rate after RYGB during normoglycemia were associated with weight loss and improved systemic insulin sensitivity.

Conclusion

Using dynamic FDG-PET, we show region-specific patterns of changes in glucose utilization following RYGB. In the hypothalamus, glucose uptake during normoglycemia tended to rise after RYGB while it was reduced in cortical regions involved in behavioral control. Following RYGB, the hypothalamus and amygdala, in contrast to other regions, displayed trends of reduced glucose uptake during hypoglycemia. These pilot results highlight the brain effects of RYGB and suggest behavioral and neuroendocrine adaptations which contribute to its antidiabetic effects.

Aims/hypothesis

Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investigate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet low in energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the global and tissue-specific level in individuals with obesity but not diabetes.

Methods

In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding, sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery (n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTT and hyperinsulinaemic–euglycaemic clamps during which concomitant simultaneous whole-body [18F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change.

Results

One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight (mean ± SD: −7.7±1.4 kg and −7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units). HOMA-IR, a main endpoint, was significantly reduced following OS (−26.3% [95% CI −49.5, −3.0], p=0.009) and non-significantly following LCD (−20.9% [95% CI −58.2, 16.5). For both groups, there were similar reductions in triglycerides and LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was an increase in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsulinaemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduced uptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery or LCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected.

Conclusions/interpretation

The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone. Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes following OS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks.

Aims/hypothesis

Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investi-gate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet lowin energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the globaland tissue-specific level in individuals with obesity but not diabetes.

Methods

In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding,sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery(n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTTand hyperinsulinaemic–euglycaemic clamps during which concomitant simultaneous whole-body [ 18 F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change.

Results

One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight(mean ± SD: −7.7±1.4 kg and −7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units).HOMA-IR, a main endpoint, was significantly reduced following OS (−26.3% [95% CI −49.5, −3.0], p=0.009) and non-significantly following LCD (−20.9% [95% CI −58.2, 16.5). For both groups, there were similar reductions in triglyceridesand LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was anincrease in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsuli-naemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduceduptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery orLCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected.

Conclusions/interpretation

The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone.Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes followingOS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks.

Trial registration

ClinicalTrials.gov NCT02988011

Funding

This work was supported by AstraZeneca R&D, the Swedish Diabetes Foundation, the European Union’s Horizon Europe Research project PAS GRAS, the European Commission via the Marie Sklodowska Curie Innovative Training Network TREATMENT, EXODIAB, the Family Ernfors Foundation, the P.O. Zetterling Foundation, Novo Nordisk Foundation, the Agnes and Mac Rudberg Foundation and the Uppsala University Hospital ALF grants

Introduction

Roux-en-Y gastric bypass (RYGB) leads to beneficial effects on glucose homeostasis, and attenuated hormonal counterregulatory responses to hypoglycemia are likely to contribute. RYGB also induces alterations in neural activity of cortical and subcortical brain regions. We aimed to characterize RYGB-induced changes in resting-state connectivity of specific brain regions of interest for energy homeostasis and behavioral control during hypoglycemia.

Method

Ten patients with BMI > 35 kg/m2 were investigated with brain PET/MR imaging during a hyperinsulinemic normo- and hypoglycemic clamp, before and 4 months after RYGB. Hormonal levels were assessed throughout the clamp. Resting-state (RS) fMRI scans were acquired in the glucose-lowering phase of the clamp, and they were analyzed with a seed-to-voxel approach.

Results

RS connectivity during initiation of hypoglycemia was significantly altered after RYGB between nucleus accumbens, thalamus, caudate, hypothalamus and their crosstalk with cortical and subcortical regions. Connectivity between the nucleus accumbens and the frontal pole was increased after RYGB, and this was associated with a reduction of ACTH (r = −0.639, p = 0.047) and cortisol (r = −0.635, p = 0.048) responses. Instead, connectivity between the caudate and the frontal pole after RYGB was reduced and this was associated with less attenuation of glucagon response during the hypoglycemic clamp (r = −0.728, p = 0.017), smaller reduction in fasting glucose (r = −0.798, p = 0.007) and less excess weight loss (r = 0.753, p = 0.012). No other significant associations were found between post-RYGB changes in ROI-to-voxel regional connectivity hormonal responses and metabolic or anthropometric outcomes.

Conclusion

RYGB alters brain connectivity during hypoglycemia of several neural pathways involved in reward, inhibitory control, and energy homeostasis. These changes are associated with altered hormonal responses to hypoglycemia and may be involved in the glucometabolic outcome of RYGB.

Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.

Background Catecholamine-stimulated lipolysis is reduced with aging, which may promote adiposity and insulin resistance. Organic cation transporter 3 (OCT3), which is inhibited by estradiol (E2), mediates catecholamine transport into adipocytes for degradation, thus decreasing lipolysis. In this study, we investigated the association of OCT3 mRNA levels in subcutaneous adipose tissue (SAT) with aging and markers of insulin resistance in women.Methods SAT biopsies were obtained from 66 women with (19) or without (47) type 2 diabetes (age 22-76 years, 20.0-40.1 kg/m2). OCT3 mRNA and protein levels were measured for group comparisons and correlation analysis. SAT was incubated with E2 and OCT3 mRNA levels were measured. Associations between OCT3 single nucleotide polymorphisms (SNPs) and diabetes-associated traits were assessed.Results OCT3 mRNA and protein levels in SAT increased with aging. SAT from postmenopausal women had higher levels of OCT3 than premenopausal women, and there was a dose-dependent reduction in OCT3 mRNA levels in SAT treated with E2. OCT3 mRNA levels were negatively associated with markers of insulin resistance, and ex vivo lipolysis. OCT3 SNPs were associated with BMI, waist to hip ratio, and circulating lipids (eg, triglycerides).Conclusion OCT3 mRNA and protein levels in SAT increased with aging, and mRNA levels were negatively associated with markers of insulin resistance. E2 incubation downregulated OCT3 mRNA levels, which may explain lower OCT3 mRNA in premenopausal vs postmenopausal women. High OCT3 protein levels in adipose tissue may result in increased catecholamine degradation, and this can contribute to the reduction in lipolysis observed in women with aging.