No description available.

Maintenance of body temperature is one of the first and most important physiological processes that must be initiated after birth. Failure to sustain homeothermy leads to hypothermia and death. Indeed, in sheep, 40% of non-predator lamb deaths are attributed to cold and cold-related causes. Brown adipose tissue (BAT) is an essential mediator of thermogenesis in many species and is responsible for 50% of the heat generated in the newborn lamb despite comprising only 2% of body weight. Previously, we found that maternal arginine supplementation increased fetal peri-renal BAT by 62%. This observation led us to test the hypothesis that increased the amount of fetal BAT will enhance neonatal thermogenesis at birth and thus combat the effects of cold stress. Thirty-one multiparous Suffolk ewes gestating singletons and twins were assigned to receive either intravenous injections of L-arginine (27 mg/kg bodyweight; n=17) or sterile saline (n=14) three times daily from Day 75 to Day 125 of gestation (term=147). Following parturition lambs were removed from their dams, placed in a thermoneutral environment, and fed artificial colostrum on a per body weight basis. At 4 hours of age, lambs were cold challenged at 0 degrees C for 2 hours. Rectal temperatures were recorded at 15 minute intervals. At 6 hours of age all singletons and one lamb of each twin pair was sacrificed. The remaining twin lamb was challenged again at 22 hours of age for an additional 2 hours prior to necropsy. Rectal temperature was greater for the duration of both cold challenges in lambs from arginine-treated ewes than lambs from saline-treated ewes (P<0.050). Interestingly, at time of necropsy, BAT weight did not differ (P>0.10) between treatments. UCP1 mRNA levels were not affected by treatment or age (P>0.10). However, TEK, PPARGC1A, NRF1, NRF2, PPARG, ADRB3, ARG2, RPS6KA1, EIF4EBP1, ODC1 were not affected by treatment (P>0.10) but were upregulated (P<0.05) by age; being greater at 24 hours of age versus 6 hours of age. Results indicate that maternal arginine treatment results in increased neonatal thermogenesis after birth. Although the underlying mechanisms remain to be elucidated, the data reported herein represent the first step in improving neonatal survival in response to cold.

No description available.

Abstract Background: The discovery of brown adipose tissue (BAT) in adults has sparked interest in its role as a therapeutic target in metabolic disorders. Preliminary studies have indicated that infrared thermography may be a promising way to quantify this thermogenic organ, which in humans is located primarily in the supraclavicular area and is activated by cold. However, ways to standardize infrared thermography methodology and to ensure measurements are reproducible have not been established. Objective: This study aims to establish a standardized and reproducible protocol to measure a thermal response to cold in the supraclavicular area. Method: In phase 1 of the study, thermal images of the supraclavicular area were taken on 3 occasions in 28 healthy adult males with mean age 23.95 ±5.87 years and mean BMI 25.20 ±3.93 kg/m2 who demonstrated a 100kcal/d increase in energy expenditure when exposed to 12ºC; a temperature known to increase BAT activity without shivering. During the first and second visits, participants were acclimated for 1 hour at 32ºC and room temperature (20-23ºC) respectively, followed by a 1 hour period of torso cold exposure at 12ºC using a cooling blanket. The third visit consisted of taking thermal images at room temperature over two hours. Body composition was measured with DEXA scanner. In phase 2, 3 trials of 32ºC acclimation followed by 12ºC cold exposure (32ºC-cold) were studied in 14 healthy adult males (mean age 20.93 ±2.4 years and mean BMI 23.55 ±3.15 kg/m2) for repeatability. The outdoor temperature on the morning of each visit was recorded from the website http://climate.weather.gc.ca in both phases. Results: In phase 1 the supraclavicular temperature stabilized after 45 minutes of acclimation at 32ºC and then rose abruptly with cooling, plateauing at 10 minutes. The change in supraclavicular temperature in response to cooling was greater after 32ºC compared to room temperature acclimation (0.22 ±0.19 vs 0.13±0.17ºC, p=0.053). There was no relation between outdoor temperature on the morning of the visit and the 32°C-cold thermal response (r=-0.18, p=0.14). The 32ºC-cold thermal response did not correlate with cervical and supraclavicular fat in 25 young males with BMI between 19.3-32.3 kg/m2 (r=-0.26, p=0.21). In phase 2, the thermal response after 32ºC acclimation was reproducible [intraclass correlation coefficient of 0.69 (0.14-0.72)]. Conclusion: Acclimation at 32ºC produces a greater and earlier response to cold in the supraclavicular area than room temperature acclimation. The thermal response after 32ºC acclimation is reproducible and unlikely to be affected by outdoor temperature and subcutaneous fat in the neck. These data suggest that the use of infrared thermography using the 32ºC-cold protocol may be effective for detecting the metabolic activity of brown adipose tissue. / Thesis / Master of Science (MSc)

Brown adipose tissue (BAT) is a unique organ in existence in mammals. It can induce non-shivering thermogenesis to control body temperature and energy balance through the expression of uncoupling protein 1 (UCP1). In our study, we aimed to evaluate the prevalence of BAT, as detected by fluorine 18-fluorodeoxyglucose (18F-FDG) positron emission tomography combined computer tomography (PET/CT), in a Hong Kong Chinese population. We also assessed the influence of age and sex to BAT in Hong Kong Chinese population. We also determined the factors associated with it, in particular, its relationship with overweight and other metabolic disorders such as diabetes mellitus. We analyzed 1765 consecutive 18F-FDG PET-CT scans of 1442 Chinese for the presence of BAT. Comparison of the variables between positive and negative BAT scans was performed using Student’s t-test. The association between maximum value of standardized uptake value (SUVmax) and variables were explored by Spearman correlation. The predictors of observed BAT were analyzed by multiple logistic regression to determine the significant predictors of positive BAT. The relationship between the monthly numbers of subjects with BAT and the respective mean monthly outdoor temperature was evaluated by Pearson’s correlation co-efficient. P < 0.05 was considered to be statistically significant. Brown adipose tissue was detected in 66 out of 1442 subjects (4.6%). BAT was significantly more commonly found in younger (43.7±13.5 years old vs. 61.4±14.2 years old, P<0.001) and female (59% vs. 46%, P<0.05) subjects. BAT also existed more frequently in subjects with lower body mass index (BMI) (21.2±3.1 kg/m2 vs. 22.4±3.7 kg/m2, P<0.01) and lower blood glucose level (5.9±0.9 mmol/L vs. 6.4±1.6 mmol/L, P<0.01). Also, BAT was detected only in subjects with no history of diabetes meallitus (DM) (0 vs. 10%, P<0.01). Moreover, lower outdoor temperature (21.6±4.6。C vs. 23.4±4.7。C, P<0.005) resulted in higher prevalence of detected BAT. In the multiple logistic regression test, age and mean monthly temperatures were the significant independent predictors of the presence of BAT (P< 0.001 and P=0.001). Age was also significantly correlated to SUVmax (P< 0.001). The monthly prevalence of positive BAT correlated negatively with mean monthly temperature by Pearson’s correlation (r = -0.79; P<0.01). To summarize, BAT was more commonly found in young, female subjects with lower BMI and blood glucose levels, and non-diabetes subjects. Age was the most important factor associated with the prevalence of BAT in humans. Lower outdoor temperature in winter can increase the prevalence of BAT even in Hong Kong’s sub-tropical climates. Also, there was an association of BAT with normal BMI (<=23) and lower blood sugar levels supporting the notion that BAT may potentially be a therapeutic target for obesity and diabetes. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Thesis (M.S.)--Florida State University, 2003. / Advisor: Dr. J. Michael Overton, Florida State University, College of Human Sciences, Dept. of Nutrition, Food and Exercise Sciences. Title and description from dissertation home page (viewed Aug. 27, 2004). Includes bibliographical references.

Thesis (Ph. D.)--University of Chicago, Committee on Human Nutrition and Nutritional Biology, August 2002. / Includes bibliographical references. Also available on the Internet.

Inhibiting peripheral serotonin (5-HT) synthesis has been shown to prevent the development of diet-induced obesity, glucose intolerance, insulin resistance and hepatic lipid deposition and to increase brown adipose tissue (BAT) thermogenic capacity. This thesis investigated 1) what effects 5-HT has on brown adipocytes (BAs), 2) if 5-HT and/or selective serotonin reuptake inhibitors (SSRIs) impair BAT function, 3) if 5-HT directly inhibits BA via a receptor-mediated mechanism, 4) which 5-HT receptor is predominantly expressed in BAT, 5) if 5-HT receptor antagonism improves BAT function and 6) if 5-HT receptor inhibition reduces SSRI induced weight gain. In murine BAs, 5-HT at concentrations ≥100 μM acutely reduced lipolysis, lipid accumulation and glycolytic flux but did not impair oxygen consumption; whereas 10 nM 5-HT reduced Ucp1 promoter activity via an extracellular receptor-mediated mechanism. Acute injection of 5-HT or the selective serotonin reuptake inhibitor (SSRI) Paroxetine decreased BA T thermogenic capacity and energy expenditure (EE), respectively. Mice lacking the serotonin transporter gene (Slc6a4-/- mice) had increased adiposity, decreased locomotor activity and increased food intake. However, male Slc6a4-/- mice had increased BAT thermogenic capacity, in contrast to the reduced EE expenditure following acute administration of Paroxetine. Using, RNA-Seq analysis and measurements of canonical 5-HT receptor second messengers (i.e. Ca2+ and cAMP transients), 5-HT2A was identified as the highest expressed 5-HT receptor in murine and human BAs and the only detected active 5-HT receptor in murine BAs. Genetic elimination of 5-HT2A prevented 5-HT induced increases in Ca2+ transient peaks and decreases in Ppargc1a mRNA expression in cultured BAs. In vivo ablation of 5-HT2A in adipose tissue increased BAT thermogenic capacity. Furthermore, in silico analyses predicted that pharmacological inhibition of 5- HT2A would induce a thermogenic program. In vitro, 5-HT2A receptor antagonists eliminated 5-HT induced Ca2+ transients and in vivo, a single injection of a peripherally-restricted 5-HT2A antagonist (Xylamidine) prevented 5-HT-induced impairments in BAT-mediated EE. Chronic administration of Xylamidine to chow- fed mice for 5-weeks improved BA T thermogenesis. Co-administration of Xylamidine with Paroxetine, however, did not attenuate Paroxetine-induced weight gain but did improve BAT functional capacity Therefore, 5-HT2A antagonism improves BAT thermogenic capacity but does not increase EE. This represents a novel therapeutic approach for increasing thermogenic capacity that may be used in conjunction with BAT activating strategies to increase EE and attenuate obesity. / Thesis / Doctor of Philosophy (PhD) / Obesity is a growing global pandemic caused by excessive energy intake over energy expenditure (EE). Some medications, such as certain selective serotonin (5-HT) reuptake inhibitor (SSRI) type antidepressants, also contribute to weight gain via reasons which are not fully understood. Currently available weight- loss medications decrease energy intake but do not affect EE. Recently, inhibiting the production of 5-HT outside the brain decreased weight gain in a model of obesity. Furthermore, this was associated with an improvement in the activity of a specialized type of adipose tissue, called brown adipose tissue (BAT). BAT is capable of expending energy in the form of thermogenesis and thus when active increases energy expenditure. We hypothesized that 5-HT impairs BAT activity and that blocking 5-HT activity may reduce weight gain in a model of antidepressant- induced weight gain. Herein, we investigated whether elevating 5-HT or increasing 5-HT downstream signaling modified BAT activity, which 5-HT receptor(s) is/are predominantly expressed in brown adipocytes (BAs), and what the effect on BAT would be if this/these receptors were eliminated. We found that in cell culture “supraphysiological” doses of 5-HT acutely impaired BA lipid mobilization and glucose metabolism; whereas, circulating concentrations of 5-HT impaired expression of select mitochondrial genes when serotonin transport was reduced. In mice, acute injections of high dose 5-HT attenuated BAT activity in response to an adrenergic stimulus. Acute treatment with an SSRI decreased EE and locomotor activity. Mice genetically lacking the serotonin transporter (the target of SSRIs) had increased weight gain (particularly fat mass), increased food intake and reduced locomotor activity, but improved BAT functional capacity. We subsequently identified that the predominantly expressed and active receptor in BAs was the 5- HT2A receptor. Genetically eliminating the 5-HT2A receptor in BAs prevented 5- HT’s reduction of a major mitochondrial gene expression regulator and improved BAT functional capacity in mice. Inhibiting 5-HT2A with a 5-HT2A brain impermeable antagonist, Xylamidine, increased BAT functional capacity in mice. Treating mice with Paroxetine (Paxil®), a SSRI known to increase weight gain, and Xylamidine did not attenuate Paroxetine-induced weight gain nor increase EE but did improve BAT functional capacity. In conclusion, we found that 1) chronic treatment with physiological levels of 5-HT impaired BAT functional capacity, 2) elimination/inhibition of adipocyte 5-HT2A improved BAT functional capacity in vivo and 3) inhibiting peripheral 5-HT2A alone did not attenuate Paroxetine- induced weight gain.

Thesis (Ph. D.)--Ohio State University, 2007. / Includes bibliographical references (p. 139-160).

Obesity is a grave disease that is increasing in global prevalence. Aberrant neuronal DNA methylation patterns have been implicated in the promotion of obesity development, but the role of neuronal DNA methyltransferases (Dnmts; enzymes that catalyze DNA methylation) in energy balance remains poorly understood. We investigated the role of neuronal Dnmt1 in normal energy regulation and obesity development using a novel Dnmt1 knockout mouse model, Dnmt1fl/fl Synapsin1Cre (ND1KO), which specifically deletes Dnmt1 in neurons. ND1KO and fl/fl control littermates were fedeither a standard chow diet or a high fat diet (HFD). We conducted a deep analysis to characterize both peripheral and central aspects of the ND1KO phenotype. We found that neuronal Dnmt1 deficiency reduced adiposity in chow-fed mice and attenuated obesity in HFD-fed male mice. ND1KO male mice had reduced food intake and increased energy expenditure on the HFD. Furthermore, these mice had improved insulin sensitivity as measured by an insulin tolerance test. HFD-fed ND1KO mice had smaller fat pads and an upregulation of thermogenic genes in brown adipose tissue. These data suggest that neuronal Dnmt1 deletion increased diet-induced thermogenesis, which may explain the lean phenotype in HFD-fed ND1KO mice. Interestingly, we found that ND1KO male mice had elevated estrogen receptor-α gene expression in the hypothalamus, which previously has been shown to control body weight. Immunohistochemistry experiments revealed that estrogen receptor-α (ERα) protein expression was upregulated in the dorsomedial region of the VMH (VMHdm), a region which may mediate the central effect of leptin. Finally, we tested whether ND1KO mice had reduced methylation of the ERα gene promoter, which might explain the ERα upregulation. Neuronal Dnmt1 deficiency decreased methylation at two CpG sites on Exon A in chow-fed mice. Collectively, these data suggest that neuronal Dnmt1 regulates energy homeostasis through pathways controlling food intake and energy expenditure, and that ERα in the VMHdm may mediate these effects.