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The ventromedial hypothalamic nucleus (VMH) is an important central effector site involved in activating brown adipose tissue (BAT) or non-shivering thermogenesis. VMH neurons have previously been shown to be thermally responsive to changes in local temperature of the preoptic area/anterior hypothalamus (PO/AH). However, the thermoresponsiveness of VMH neurons of room temperature acclimatized and cold acclimatized rats to peripheral thermal stimulation has not been tested. In this thesis, a series of studies was designed to determine the thermoresponsiveness of VMH neurons to peripheral (scrotal) thermal stimulation of rats. Extracelluiar VMH neuronal activity was recorded from urethane anaesthetized male Sprague-Dawley rats, which were acclimatized either to room temperature (21°C for 4 weeks) or to cold (4°C for 4 weeks) prior to testing, during scrotal cooling and heating with glass-micropipettes filled with 0.5 M sodium acetate containing 2% pontamine sky blue. The rats' colonic temperatures were kept at normothermia (37°C), or hypothermia (33-35°C) during scrotal thermal stimulation. In the room temperature acclimatized rats, VMH neurons were temperature responsive to scrotal heating and cooling and were classified as warm responsive (WRN), cold responsive (CRN) and temperature non-responsive neurons (TNRN), based on their thermal coefficients. The ratio of VMH WRNs and CRNs was similar to that of thermoresponsive neurons observed in other brain regions (eg, the PO/AH and thalamus). VMH WRNs and CRNs were further classified as biphasic or monophasic in nature according to their thermal responses to scrotal heating and cooling. VMH neurons sustained their thermoresponsiveness to repeated trials of scrotal thermal stimulation with colonic temperatures maintained at 37°C or when colonic temperatures were acutely lowered from 37°C to 35°C and 33°C. In addition, scrotal thermal signals specifically altered neuronal activity of VMH thermoresponsive neurons, as changes in EEG activity did not occur with changes in VMH neuronal activity. Scrotal thermal inputs were functionally shown to be transmitted via the medial preoptic nucleus (MPO) prior to reaching the VMH nucleus because thermoresponsive VMH neuronal activity was blocked with the pretreatment of lidocaine into the MPO. Scrotal heating or cooling to 21°C-acclimatized rats did not increase IBAT temperatures, inferring that scrotal cooling had not evoked IBAT thermogenesis in this group. In cold acclimatized (CA) rats, prolonged (over 2 hours) and transient localized scrotal cooling caused IBAT temperatures to increase, inferring that scrotal cooling activated BAT thermogenesis. Mean basal firing rates of all recorded VMH neurons of CA-groups significantly increased, compared to those of VMH neurons observed in room temperature acclimatized (RA) groups. More VMH CRNs than WRNs were recorded in the CA-group and the thermoresponsiveness (ie, thermal coefficient) of VMH CRNs significantly increased during localized scrotal cooling in the cold acclimatized group, compared to thermal coefficients of VMH CRNs of the RA-groups. (Abstract shortened by UMI.)

Both white and brown adipose tissues exhibit extensive vascularity. Increased angiogenesis in brown adipose tissue (BAT) is crucial for brown fat activation and thermogenesis in animals during cold acclimation. BAT can be similarly activated by food intake to generate heat through cellular respiration, in a process known as diet induced thermogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates both pathological and physiological angiogenesis and can stimulate cell proliferation, migration, survival and vessel permeability. However, VEGF has also been shown to affect an increasing number of non-vascular cells such as skeletal muscle and kidney podocytes. The expression and function of VEGF in white and brown adipocytes are not fully understood. We have previously shown that the expression of VEGF is concomitantly regulated with skeletal muscle differentiation. Here we show that VEGF is expressed in BAT and all major white adipose depots in mice. VEGF expression was increased during white and brown adipocyte differentiation and was regulated in cultured brown adipocytes by the \(PPAR\gamma\) agonist troglitazone and by \(PGC1\alpha\) in BAT in vivo. Systemic VEGF neutralization led to brown adipocyte apoptosis in vivo, loss of mitochondrial cristae and increased mitophagy and was associated with increased inflammation and fibrosis. VEGFR2 was expressed in both brown preadipocytes and adipocytes. Blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis in vitro. VEGF also functioned as a mitogen and survival factor for brown preadipocytes. VEGF 164 and VEGF 188, isoforms that can bind heparan sulfate proteoglycans, comprise >98% of total VEGF in BAT, subcutaneous and perigonadal fat depots. Embryos that lacked VEGF 164 and 188 displayed abnormal BAT development with fewer brown adipocytes, lower levels of mitochondrial uncoupling protein 1 and Cox IV. These results indicate a direct role for VEGF signaling in brown adipocytes and preadipocytes and suggest the importance of heparan sulfate binding VEGF isoforms in BAT development. Elucidation of the role of VEGF signaling in adipocytes is vital to understanding adipose tissue expansion and activation and may reveal novel therapeutic targets for the activation of brown fat in humans.

More than 30% of the population suffers from obesity, which increases the risk of death and secondary health problems. Body fat [white adipose tissue (WAT) and brown adipose tissue (BAT)] are innervated and regulated by the sympathetic nervous system (SNS). WAT stores energy, while BAT generates heat for thermoregulation. Fat also has sensory innervations, but the roles of sensory nerves are still being elucidated. Hence, understanding the neuroanatomy of the SNS innervations of fat and the neural regulation of fat metabolism will be valuable for advancing obesity treatment. Using trans-synaptic tract tracers with unique fluorescent proteins, we defined and compared the SNS innervations of visceral fat [mesenteric WAT (MWAT)] and subcutaneous fat [inguinal WAT (IWAT)] and of IWAT and interscapular BAT (IBAT) in Siberian hamsters. MWAT and IWAT have moderately shared SNS innervations within the hindbrain, but separate SNS innervations in rostral regions. In contrast, IWAT and IBAT have relatively separate SNS circuitries throughout the brain yet some overlap in SNS nuclei known to regulate thermogenesis. We tested for the presence of functional coordination between IWAT and IBAT defined by overlap in IWAT SNS and IBAT SNS innervations. When IBAT function was impaired by SNS denervation, IWAT SNS drive, thermogenic activity, and beige adipocyte recruitment increased in cold exposed hamsters likely through coordination with IWAT SNS pathways. Conversely, we found that only SNS drive to IWAT increased during acute food deprivation suggesting that populations of SNS neurons singly innervating each fat depot may contribute to differential SNS drive to fat. Lastly, we demonstrated that IWAT sensory nerves mediate the functional coordination between IWAT and IBAT and the regulation of SNS drive to fat. The absence of IWAT sensory feedback via sensory denervation differentially decreased SNS drive to IBAT and IWAT itself, but not to MWAT, retroperitoneal WAT, and epididymal WAT in cold exposed hamsters. Collectively, the studies in this dissertation provide neuroanatomical evidence of separate and shared SNS brain sites likely receiving sensory signaling and regulating SNS drive to fat, and direct evidence of the roles of SNS and sensory nerves innervating fat to energetic homeostasis and thermoregulation.

\(PGC1\alpha\) is a key transcriptional coregulator of mitochondrial biogenesis, oxidative metabolism and thermogenesis. We developed a quantitative high throughput screen to identify small molecules that can induce \(PGC1\alpha\) expression in adipocytes. Small molecules antagonizing the TRPVs (Transient Receptor Potential Vanilloid), a family of ion channels, induced \(PGC1\alpha\) expression in adipocytes. In particular, inhibition of TRPV4 increased expression of \(PGC1\alpha\), UCP1 and cellular respiration; conversely, chemical activation of TRPV4 repressed this pathway. Blocking TRPV4 in cultured adipocytes also reduced the expression of multiple proinflammatory genes that are involved in the development of insulin resistance. These effects of TRPV4 were mediated by the activation of ERK1/2. Finally, mice with a null mutation for TRPV4 showed higher energy expenditure with no change in movement or food intake, and were protected from diet-induced obesity, adipose inflammation and insulin resistance. This study links TRPV4 to robust pathways that offer therapeutic potential in obesity and related metabolic diseases.

16 Abstract The rising prevalence in noncommunicable diseases worldwide calls for the effort to determine their underlying causes. Common metabolic disorders in particular overwhelm the healthcare systems and are a one of the leading causes of poor quality of life of patients. Metabolic syndrome is represented by concurrence of several conditions - dyslipidaemia, obesity, hypertension or impaired glucose tolerance - altered metabolic phenotypes related to genetic and environmental factors. Recent studies suggest that early-life exposure to certain environmental stimuli is particularly capable of changing the mammalian phenotypes. Nutrition, as one of the major factors influencing health, is naturally a focus of research, which studies the link between parental diets and phenotypic alterations in offspring. The developmental origins of health and disease were historically more focused on maternal undernutrition, it is, however, more important to focus on surplus of macronutrients considering the westernization of modern diets. We propose the relevancy of not only the amount of macronutrients in maternal diet, but also their sources, as they may increase disease risk in offspring. Here we report, that sucrose as an alternative carbohydrate in maternal diet, has a marked impact on metabolism of the offspring...

Background: Hibernomas are rare benign soft-tissue tumours arising from brown fat tissue. Although imaging characteristics are not specific certain imaging features, common locations and patient demographics may suggest hibernoma as a differential diagnosis. Case presentation: We report on two 48-year-old male patients with hibernoma. The tumour presented with local swelling of the inguinal region in the first patient and was an incidental imaging finding in the second patient. Imaging included magnetic resonance imaging in both patients and computed tomography as well as 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in the second patient. In both cases histological diagnosis was initially based on excisional and needle core biopsy, respectively. Complete surgical resection confirmed the diagnosis of hibernoma thereafter. Conclusion: In soft tissue tumours with fatty components hibernoma may be included into the differential diagnosis. Because of the risk of sampling errors in hibernoma-like tissue components of myxoid and well-differentiated liposarcoma, complete resection is mandatory. This article also reviews the current imaging literature of hibernomas.

Background: Hibernomas are rare benign soft-tissue tumours arising from brown fat tissue. Although imaging characteristics are not specific certain imaging features, common locations and patient demographics may suggest hibernoma as a differential diagnosis. Case presentation: We report on two 48-year-old male patients with hibernoma. The tumour presented with local swelling of the inguinal region in the first patient and was an incidental imaging finding in the second patient. Imaging included magnetic resonance imaging in both patients and computed tomography as well as 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in the second patient. In both cases histological diagnosis was initially based on excisional and needle core biopsy, respectively. Complete surgical resection confirmed the diagnosis of hibernoma thereafter. Conclusion: In soft tissue tumours with fatty components hibernoma may be included into the differential diagnosis. Because of the risk of sampling errors in hibernoma-like tissue components of myxoid and well-differentiated liposarcoma, complete resection is mandatory. This article also reviews the current imaging literature of hibernomas.