Basal and cold-induced fatty acid uptake of human brown adipose tissue is impaired in obesity

atty acids (FA) are important substrates for brown adipose tissue (BAT) metabolism, however, it remains unclear whether there exists a difference in FA metabolism of BAT between lean and obese healthy humans. In this study we evaluated supraclavicular BAT fatty acid uptake (FAU) along with blood perfusion in lean and obese subjects during cold exposure and at room temperature using positron emission tomography (PET)/computed tomography (CT). Additionally, tissue samples were taken from supraclavicular region (typical BAT region) from a subset of subjects to evaluate histological presence of BAT. Non-shivering cold stress elevated FAU and perfusion of BAT in lean, but not in obese subjects. Lean subjects had greater FAU in BAT compared to obese subjects during cold exposure and interestingly also at room temperature. The higher BAT FAU was related to younger age and several indicators of superior systemic metabolic health. The subjects who manifested BAT histologically had several folds higher BAT FAU compared to subjects with no such histological manifestation. Together, obese subjects have less active tissue in supraclavicular region both in basal and cold-activated state and the FA metabolism of BAT is blunted in obesity.</p

Radiosynthesis and Preclinical Evaluation of an α2A-Adrenoceptor Tracer Candidate, 6-[18F]Fluoro-marsanidine

Purpose: The α2-adrenoceptors mediate many effects of norepinephrine and epinephrine, and participate in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. Of the three receptor subtypes, only α2A and α2C are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α2-adrenoceptors has been limited to the α2C subtype. Here, we report the synthesis of 6-[18F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α2A-adrenoceptors, and its preclinical evaluation in rats and mice.Procedures: 6-[18F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [18F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α2A-knockout (KO) and wild-type (WT) mice for subtype selectivity. In vivo PET imaging and ex vivo brain autoradiography were performed to determine the tracer distribution in the brain. The specificity of the tracer for the target was determined by pretreatment with the subtype-non-selective α2-agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[18F]fluoro-marsanidine were also analyzed.Results: 6-[18F]Fluoro-marsanidine was synthesized with [18F]Selectfluor bis(triflate) in a radiochemical yield of 6.4 ± 1.7 %. The molar activity was 3.1 to 26.6 GBq/μmol, and the radiochemical purity was > 99 %. In vivo studies in mice revealed lower uptake in the brains of α2A-KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α2A-adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[18F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice.Conclusion: 6-[18F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α2A-adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[18F]fluoro-marsanidine unsuitable for α2A-adrenoceptor targeting in rodents in vivo.</p

Comparison of high and low molar activity TSPO tracer [18F]F-DPA in a mouse model of Alzheimer’s disease

[18F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (Am’s). In certain cases, low Am can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [18F]F-DPA resulting in high Am (990 ± 150 GBq/µmol) and performed in vivo comparison with low Am (9.0 ± 2.9 GBq/µmol) [18F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing Am on specific binding. The differing injected masses affect the washout profile and shape of the time–activity curves. Ratios of standardized uptake values obtained with high and low Am [18F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high Am [18F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high Am was used.</p

Obesity risk is associated with altered cerebral glucose metabolism and decreased μ-opioid and CB1 receptor availability

BackgroundObesity is a pressing public health concern worldwide. Novel pharmacological means are urgently needed to combat the increase of obesity and accompanying type 2 diabetes (T2D). Although fully established obesity is associated with neuromolecular alterations and insulin resistance in the brain, potential obesity-promoting mechanisms in the central nervous system have remained elusive. In this triple-tracer positron emission tomography study, we investigated whether brain insulin signaling, μ-opioid receptors (MORs) and cannabinoid CB1 receptors (CB1Rs) are associated with risk for developing obesity.MethodsSubjects were 41 young non-obese males with variable obesity risk profiles. Obesity risk was assessed by subjects’ physical exercise habits, body mass index and familial risk factors, including parental obesity and T2D. Brain glucose uptake was quantified with [18F]FDG during hyperinsulinemic euglycemic clamp, MORs were quantified with [11C]carfentanil and CB1Rs with [18F]FMPEP-d2.ResultsSubjects with higher obesity risk had globally increased insulin-stimulated brain glucose uptake (19 high-risk subjects versus 19 low-risk subjects), and familial obesity risk factors were associated with increased brain glucose uptake (38 subjects) but decreased availability of MORs (41 subjects) and CB1Rs (36 subjects).ConclusionsThese results suggest that the hereditary mechanisms promoting obesity may be partly mediated via insulin, opioid and endocannabinoid messaging systems in the brain.</p

Increased Brain Fatty Acid Uptake in Metabolic Syndrome

OBJECTIVE: To test whether brain fatty acid uptake is enhanced in obese subjects with metabolic syndrome (MS) and whether weight reduction modifies it. RESEARCH DESIGN AND METHODS: We measured brain fatty acid uptake in a group of 23 patients with MS and 7 age-matched healthy control subjects during fasting conditions using positron emission tomography (PET) with [(11)C]-palmitate and [(18)F]fluoro-6-thia-heptadecanoic acid ([(18)F]-FTHA). Sixteen MS subjects were restudied after 6 weeks of very low calorie diet intervention. RESULTS: At baseline, brain global fatty acid uptake derived from [(18)F]-FTHA was 50% higher in patients with MS compared with control subjects. The mean percentage increment was 130% in the white matter, 47% in the gray matter, and uniform across brain regions. In the MS group, the nonoxidized fraction measured using [(11)C]-palmitate was 86% higher. Brain fatty acid uptake measured with [(18)F]-FTHA-PET was associated with age, fasting serum insulin, and homeostasis model assessment (HOMA) index. Both total and nonoxidized fractions of fatty acid uptake were associated with BMI. Rapid weight reduction decreased brain fatty acid uptake by 17%. CONCLUSIONS: To our knowledge, this is the first study on humans to observe enhanced brain fatty acid uptake in patients with MS. Both fatty acid uptake and accumulation appear to be increased in MS patients and reversed by weight reduction

In Vivo Availability of Cannabinoid 1 Receptor Levels in Patients with First-Episode Psychosis

Importance: Experimental and epidemiological studies implicate the cannabinoid 1 receptor (CB1R) in the pathophysiology of psychosis. However, whether CB1R levels are altered in the early stages of psychosis and whether they are linked to cognitive function or symptom severity remain unknown.Objective: To investigate CB1R availability in first-episode psychosis (FEP) without the confounds of illness chronicity or the use of illicit substances or antipsychotics.Design, Setting, and Participants: This cross-sectional, case-control study of 2 independent samples included participants receiving psychiatric early intervention services at 2 independent centers in Turku, Finland (study 1) and London, United Kingdom (study 2). Study 1 consisted of 18 volunteers, including 7 patients with affective or nonaffective psychoses taking antipsychotic medication and 11 matched controls; study 2, 40 volunteers, including 20 antipsychotic-naive or antipsychotic-free patients with schizophrenia or schizoaffective disorder and 20 matched controls. Data were collected from January 5, 2015, through September 26, 2018, and analyzed from June 20, 2016, through February 12, 2019.Main Outcomes and Measures: The availability of CB1R was indexed using the distribution volume (VT, in milliliters per cubic centimeter) of 2 CB1R-selective positron emission tomography radiotracers: fluoride 18–labeled FMPEP-d2 (study 1) and carbon 11–labeled MePPEP (study 2). Cognitive function was measured using the Wechsler Digit Symbol Coding Test. Symptom severity was measured using the Brief Psychiatric Rating Scale for study 1 and the Positive and Negative Syndrome Scale for study 2.Results: A total of 58 male individuals were included in the analyses (mean [SD] age of controls, 27.16 [5.93] years; mean [SD] age of patients, 26.96 [4.55] years). In study 1, 7 male patients with FEP (mean [SD] age, 26.80 [5.40] years) were compared with 11 matched controls (mean [SD] age, 27.18 [5.86] years); in study 2, 20 male patients with FEP (mean [SD] age, 27.00 [5.06] years) were compared with 20 matched controls (mean [SD] age, 27.15 [6.12] years). In study 1, a significant main effect of group on [18F]FMPEP-d2 VT was found in the anterior cingulate cortex (ACC) (t16 = −4.48; P Conclusions and Relevance: The availability of CB1R was lower in antipsychotic-treated and untreated cohorts relative to matched controls. Exploratory analyses indicated that greater reductions in CB1R levels were associated with greater symptom severity and poorer cognitive functioning in male patients. These findings suggest that CB1R may be a potential target for the treatment of psychotic disorders.</p

Use of Cis-[18F]Fluoro-Proline for Assessment of Exercise-Related Collagen Synthesis in Musculoskeletal Connective Tissue

Protein turnover in collagen rich tissue is influenced by exercise, but can only with difficulty be studied in vivo due to use of invasive procedure. The present study was done to investigate the possibility of applying the PET-tracer, cis-[18F]fluoro-proline (cis-Fpro), for non-invasive assessment of collagen synthesis in rat musculoskeletal tissues at rest and following short-term (3 days) treadmill running. Musculoskeletal collagen synthesis was studied in rats at rest and 24 h post-exercise. At each session, rats were PET scanned at two time points following injection of cis-FPro: (60 and 240 min p.i). SUV were calculated for Achilles tendon, calf muscle and tibial bone. The PET-derived results were compared to mRNA expression of collagen type I and III. Tibial bone had the highest SUV that increased significantly (p<0.001) from the early (60 min) to the late (240 min) PET scan, while SUV in tendon and muscle decreased (p<0.001). Exercise had no influence on SUV, which was contradicted by an increased gene expression of collagen type I and III in muscle and tendon. The clearly, visible uptake of cis-Fpro in the collagen-rich musculoskeletal tissues is promising for multi-tissue studies in vivo. The tissue-specific differences with the highest basal uptake in bone are in accordance with earlier studies relying on tissue incorporation of isotopic-labelled proline. A possible explanation of the failure to demonstrate enhanced collagen synthesis following exercise, despite augmented collagen type I and III transcription, is that SUV calculations are not sensitive enough to detect minor changes in collagen synthesis. Further studies including kinetic compartment modeling must be performed to establish whether cis-Fpro can be used for non-invasive in-vivo assessment of exercise-induced changes in musculoskeletal collagen synthesis

Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake

Similar to muscles, the intestine is also insulin resistant in obese subjects and subjects with impaired glucose tolerance. Exercise training improves muscle insulin sensitivity, but its effects on intestinal metabolism are not known. We studied the effects of high intensity interval training (HIIT) and moderate intensity continuous training (MICT) on intestinal glucose and free fatty acid uptake from circulation in humans. Twenty-eight healthy middle-aged sedentary men were randomized for two weeks of HIIT or MICT. Intestinal insulin-stimulated glucose uptake and fasting free fatty acid uptake from circulation were measured using positron emission tomography and [18F]FDG and [18F]FTHA. In addition, effects of HIIT and MICT on intestinal Glut2 and CD36 protein expression were studied in rats. Training improved aerobic capacity (p=0.001) and whole-body insulin sensitivity (p=0.04), but not differently between HIIT and MICT. Insulin-stimulated glucose uptake increased only after the MICT in the colon [HIIT=0%; MICT=37%] (p=0.02 for time*training) and tended to increase in the jejunum [HIIT=-4%; MICT=13%] (p=0.08 for time*training). Fasting free fatty acid uptake decreased in the duodenum in both groups [HIIT=-6%; MICT=-48%] (p=0.001 time) and tended to decrease in the colon in the MICT group [HIIT=0%; MICT=-38%] (p=0.08 for time*training). In rats, both training groups had higher Glut2 and CD36 expression compared to control animals. This study shows that already two weeks of MICT enhances insulin-stimulated glucose uptake while both training modes reduce fasting free fatty acid uptake in the intestine in healthy middle-aged men, providing an additional mechanism by which exercise training can improve whole body metabolism.</p