An evaluation of patient experience during percutaneous breast biopsy.

OBJECTIVE: Percutaneous breast biopsy in a tertiary referral high volume breast centre: can we improve the patient experience? PURPOSE: The study was performed to evaluate patient experience during ultrasound-guided (UGB) and vacuum-assisted stereotactic breast biopsy (SBB) and determine what factors could improve the patient experience. METHODS: Consecutive patients who underwent image guided breast biopsy from 01- 05/30, 2015 were approached in a structured telephone interview to evaluate pain and bruising from the procedure. Three hundred and fifty-one patients were interviewed (116 SBB and 235 UGB). Information about the radiologist performing the biopsy, biopsy type, needle gauge, and number of cores was collected from the biopsy reports. Correlation was done using Spearman rank test. RESULTS: Average patient scores of pain with UGB and SBB were 2.3 and 3.1 (out of 10). There was a significant correlation between pain during SBB and physician experience (p = 0.013), and no correlation with pain during UGB (p > 0.05). No correlation was found between needle gauge and pain experienced during breast biopsy or between numbers of cores and pain (p > 0.05). Body position during SBB was mentioned to cause discomfort and pain in 28% of patients while during UGB was mentioned by 0.4% of patients. CONCLUSION: SBB was inferior to UGB for patient experience, but years of radiologists' experience correlated with improved patient scores of pain for SBB. KEY POINTS: • To achieve high quality, an institution must emphasise patient-centred care. • Increased radiologist training with stereotactic biopsy may contribute to improved patient experience. • Stereotactic breast biopsy was inferior to ultrasound biopsy for patient experience. • Radiologists' experience correlated with improved patient scores of pain for stereotactic biopsy.

Ethanol locks in the prevention and treatment of catheter-related bloodstream infections.

OBJECTIVE: To evaluate the evidence regarding the use of ethanol lock therapy (ELT) for catheter-related bloodstream infection (CRBSI) prophylaxis and treatment. DATA SOURCES: A literature search was conducted using PubMed (August 2003-January 2013) with search terms: ethanol lock, ethanol locks, ethanol lock therapy, prophylaxis, prevention, catheter-related bloodstream infection, and catheter-related infection. Additional sources were identified through a subsequent review of relevant articles. STUDY SELECTION AND DATA EXTRACTION: All English-language studies with >1 patient and a primary outcome of rates of infection, clinical cure, catheter removal or line salvage were evaluated. Studies where ELT was not used for CRBSI prophylaxis or treatment, review articles, and in vitro studies were excluded. Data were abstracted through an independent review of all articles by 2 authors. Discrepancies were discussed and resolved. DATA SYNTHESIS: 13 prophylaxis studies evaluated 617 patients; all studies reported decreased rates of infection and catheter removal with ELT. The ELT regimen associated with the most consistent benefit was 70% ethanol, a 2- to 4-hour dwell time, and daily exchange for ≥1 month. 9 treatment studies evaluated 213 catheters, with 90% (192/213) cure and 84% (179/213) line salvage. ELT was always used in combination with systemic antibiotics. The most common ELT treatment regimen was 70% ethanol, a 12- to 24-hour dwell time, and a duration of 1-5 days. No serious adverse events were reported. CONCLUSION: The current literature suggests that prophylactic ELT decreases the rates of infection and catheter removal, and ELT treatment appears efficacious in combination with systemic antibiotics.

Deep tissue multi-photon imaging using adaptive optics with direct focus sensing and shaping.

High-resolution optical imaging deep in tissues is challenging because of optical aberrations and scattering of light caused by the complex structure of living matter. Here we present an adaptive optics three-photon microscope based on analog lock-in phase detection for focus sensing and shaping (ALPHA-FSS). ALPHA-FSS accurately measures and effectively compensates for both aberrations and scattering induced by specimens and recovers subcellular resolution at depth. A conjugate adaptive optics configuration with remote focusing enables in vivo imaging of fine neuronal structures in the mouse cortex through the intact skull up to a depth of 750 µm below the pia, enabling near-non-invasive high-resolution microscopy in cortex. Functional calcium imaging with high sensitivity and high-precision laser-mediated microsurgery through the intact skull were also demonstrated. Moreover, we achieved in vivo high-resolution imaging of the deep cortex and subcortical hippocampus up to 1.1 mm below the pia within the intact brain.

Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity.

Nuclear factor E2-related factor 2 (Nrf2) is a cap-n-collar basic leucine zipper (CNC-bZIP) transcription factor that is well established as a master regulator of phase II detoxification and antioxidant gene expression and is strongly expressed in tissues involved in xenobiotic metabolism including liver and kidney. Nrf2 is also abundantly expressed in adipose tissue; however, the exact function of Nrf2 in adipocyte biology is unclear. In the current study we show that targeted knock-out of Nrf2 in mice decreases adipose tissue mass, promotes formation of small adipocytes, and protects against weight gain and obesity otherwise induced by a high fat diet. In mouse embryonic fibroblasts, 3T3-L1 cells, and human subcutaneous preadipocytes, selective deficiency of Nrf2 impairs adipocyte differentiation. Deficiency of Nrf2 also leads to decreased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT enhancer-binding protein alpha (C/EBPalpha), and their downstream targets during adipocyte differentiation. Conversely, activation of Nrf2 in 3T3-L1 cells by stable knockdown of its negative regulator Keap1 enhances and accelerates hormone-induced adipocyte differentiation. Transfection of Nrf2 stimulates Ppargamma promoter activity, and stable knockdown of Keap1 enhances PPARgamma expression in 3T3-L1 cells. In addition, chromatin immunoprecipitation studies show that Nrf2 associates with consensus binding sites for Nrf2 in the Ppargamma promoter. These findings demonstrate a novel biologic role for Nrf2 beyond its participation in detoxification and antioxidant pathways and place Nrf2 within the limited network of transcription factors that control adipocyte differentiation by regulating expression of PPARgamma.

Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer's disease transgenic mouse model.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no disease-modifying treatment. AD progression is characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta (Aß) and neurofibrillary tangles in the brain, leading to neuronal and glial dysfunctions. Neuropeptides govern diverse pathophysiological processes and represent key players in AD pathogenesis, regulating synaptic plasticity, glial cell functions and amyloid pathology. Activation of the pro-opiomelanocortin (POMC)-derived neuropeptide and its receptor from the melanocortin receptor (MCR) family have previously been shown to rescue the impairment in hippocampus-dependent synaptic plasticity in the APP/PS1 mouse model of AD. However, the functional roles of MCR signaling in AD conditions, particularly in glial functions, are largely unknown. In this study, we investigated the potential benefits of MCR activation in AD. In APP/PS1 transgenic mice, we demonstrate that MCR activation mediated by the central administration of its agonist D-Tyr MTII substantially reduces Aß accumulation, while alleviating global inflammation and astrocytic activation, particularly in the hippocampus. MCR activation prominently reduces the A1 subtype of reactive astrocytes, which is considered a key source of astrocytic neurotoxicity in AD. Concordantly, MCR activation suppresses microglial activation, while enhancing their association with amyloid plaques. The blunted activation of microglia may contribute to the reduction in the neurotoxic phenotypes of astrocytes. Importantly, transcriptome analysis reveals that MCR activation restores the impaired homeostatic processes and microglial reactivity in the hippocampus in APP/PS1 mice. Collectively, our findings demonstrate the potential of MCR signaling as therapeutic target for AD.

Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.

Outcomes after Surgery for Early Stage Breast Cancer in Women Staged With Preoperative Breast Magnetic Resonance Imaging According to Breast Tissue Density.

PURPOSE: To determine surgical outcomes and breast cancer disease-free survival outcomes of women with early stage breast cancer with and without use of preoperative breast MRI according to breast tissue density. METHODS: Women with early stage breast cancer diagnosed from 2004 to 2009 were classified into 2 groups: 1) those with dense and heterogeneously dense breasts (DB); 2) those with nondense breasts (NDB) (scattered fibroglandular and fatty replaced tissue). The 2 groups were reviewed to determine who underwent preoperative MRI. Breast tissue density was determined with mammography according to ACR BI-RADS. Patients were compared according to tumor size, grade, stage, and treatment. Survival analysis was performed using Kaplan-Meier estimates. RESULTS: In total, 261 patients with mean follow-up of 85 months (25-133) were included: 156 DB and 105 NDB. Disease-free survival outcomes were better in the DB group in patients with MRI than in those without MRI: patients with MRI had significantly fewer local recurrences (P < 0.016) and metachronous contralateral breast cancers (P < 0.001), but this was not the case in the NDB group. Mastectomies were higher in the DB group with preoperative MRI than in those without MRI (P < 0.01), as it was in the NDB group (P > 0.05). CONCLUSIONS: Preoperative breast MRI was associated with reduced local recurrence and metachronous contralateral cancers in the DB group, but not in the NDB group; however, the DB patients with MRI had higher mastectomy rates.

CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis.

OBJECTIVE: The cocaine- and amphetamine-regulated transcript (CART) codes for a pivotal neuropeptide important in the control of appetite and energy homeostasis. However, limited understanding exists for the defined effector sites underlying CART function, as discrepant effects of central CART administration have been reported. METHODS: By combining Cart-cre knock-in mice with a Cart adeno-associated viral vector designed using the flip-excision switch (AAV-FLEX) technology, specific reintroduction or overexpression of CART selectively in CART neurons in the arcuate nucleus (Arc) and lateral hypothalamic area (LHA), respectively, was achieved. The effects on energy homeostasis control were investigated. RESULTS: Here we show that CART neuron-specific reintroduction of CART into the Arc and LHA leads to distinct effects on energy homeostasis control. Specifically, CART reintroduction into the Arc of otherwise CART-deficient Cartcre/cre mice markedly decreased fat mass and body weight, whereas CART reintroduction into the LHA caused significant fat mass gain and lean mass loss, but overall unaltered body weight. The reduced adiposity in ArcCART;Cartcre/cre mice was associated with an increase in both energy expenditure and physical activity, along with significantly decreased Npy mRNA levels in the Arc but with no change in food consumption. Distinctively, the elevated fat mass in LHACART;Cartcre/cre mice was accompanied by diminished insulin responsiveness and glucose tolerance, greater spontaneous food intake, and reduced energy expenditure, which is consistent with the observed decrease of brown adipose tissue temperature. This is also in line with significantly reduced tyrosine hydroxylase (Th) and notably increased corticotropin-releasing hormone (Crh) mRNA expressions in the paraventricular nucleus (PVN). CONCLUSIONS: Taken together, these results identify catabolic and anabolic effects of CART in the Arc and LHA, respectively, demonstrating for the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis.

Arcuate nucleus and lateral hypothalamic CART neurons in the mouse brain exert opposing effects on energy expenditure.

Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the hypothalamus and an important regulator of energy homeostasis; however, the specific contributions of different CART neuronal populations to this process are not known. Here, we show that depolarization of mouse arcuate nucleus (Arc) CART neurons via DREADD technology decreases energy expenditure and physical activity, while it exerts the opposite effects in CART neurons in the lateral hypothalamus (LHA). Importantly, when stimulating these neuronal populations in the absence of CART, the effects were attenuated. In contrast, while activation of CART neurons in the LHA stimulated feeding in the presence of CART, endogenous CART inhibited food intake in response to Arc CART neuron activation. Taken together, these results demonstrate anorexigenic but anabolic effects of CART upon Arc neuron activation, and orexigenic but catabolic effects upon LHA-neuron activation, highlighting the complex and nuclei-specific functions of CART in controlling feeding and energy homeostasis.

GPR88 is a critical regulator of feeding and body composition in mice.

GPR88 is an orphan G-protein-coupled receptor with predominant expression in reward-related areas in the brain. While the lack of GPR88 has been demonstrated to induce behavioral deficits, the potential function of the receptor in the control of food intake and energy balance remains unexplored. In this work, the role of GPR88 in energy homeostasis was investigated in Gpr88 -/- mice fed either standard chow or high fat diet (HFD). Gpr88 -/- mice showed significantly reduced adiposity accompanied with suppressed spontaneous food intake, particularly pronounced under HFD treatment. While energy expenditure was likewise lower in Gpr88 -/- mice, body weight gain remained unchanged. Furthermore, deregulation in glucose tolerance and insulin responsiveness in response to HFD was attenuated in Gpr88 -/- mice. On the molecular level, distinct changes in the hypothalamic mRNA levels of cocaine-and amphetamine-regulated transcript (Cartpt), a neuropeptide involved in the control of feeding and reward, were observed in Gpr88 -/- mice. In addition, GPR88 deficiency was associated with altered expressions of the anorectic Pomc and the orexigenic Npy in the arcuate nucleus, especially under HFD condition. Together, our results indicate that GPR88 signalling is not only important for reward processes, but also plays a role in the central regulatory circuits for energy homeostasis.

Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic.

There was no statistically significant difference in clinical outcomes for patients using face-to-face and telephone anticoagulation clinics.

Temperature dependence of the control of energy homeostasis requires CART signaling.

Cocaine- and amphetamine-regulated transcript (CART) is a key neuropeptide with predominant expression in the hypothalamus central to the regulation of diverse biological processes, including food intake and energy expenditure. While there is considerable information on CART's role in the control of feeding, little is known about its thermoregulatory potential. Here we show the consequences of lack of CART signaling on major parameters of energy homeostasis in CART-/- mice under standard ambient housing (RT, 22°C), which is considered a mild cold exposure for mice, and thermoneutral conditions (TN, 30°C). WT mice kept at RT showed an increase in food intake, energy expenditure, BAT UCP-1 expression, and physical activity compared with TN condition, reflecting the augmented energy demand for thermogenesis at RT. On the molecular level, RT housing led to upregulated mRNA expression of TH, CRH, and TRH at the PVN, while NPY, AgRP and CART mRNA levels in the Arc were downregulated. CART-/- mice displayed elevated adiposity and diminished lean mass across both RT and TN. At RT, CART-/- mice showed unchanged food consumption yet greater body weight gain. In addition, an increase in energy expenditure and heightened BAT thermogenesis marked by UCP-1 protein expression was observed in the CART-/- mice. In contrast, TN-housed CART-/- mice exhibited lower weight gain than WT mice accompanied with pronounced reduction in basal feeding. These findings were correlated with reduced BAT temperature, but unchanged energy expenditure and UCP-1 levels. Interestingly, the respiratory exchange ratio for CART-/- mice, which shifted from lower at RT to higher at TN with respect to WT controls, indicates a transition of relative fuel source preference from fat to carbohydrate in the absence of CART signaling. Taken together, these results demonstrate that CART is a critical regulator of energy expenditure, energy partitioning and utilization dependent on the thermal environment.

Intermittent Moderate Energy Restriction Improves Weight Loss Efficiency in Diet-Induced Obese Mice.

BACKGROUND: Intermittent severe energy restriction is popular for weight management. To investigate whether intermittent moderate energy restriction may improve this approach by enhancing weight loss efficiency, we conducted a study in mice, where energy intake can be controlled. METHODS: Male C57/Bl6 mice that had been rendered obese by an ad libitum diet high in fat and sugar for 22 weeks were then fed one of two energy-restricted normal chow diets for a 12-week weight loss phase. The continuous diet (CD) provided 82% of the energy intake of age-matched ad libitum chow-fed controls. The intermittent diet (ID) provided cycles of 82% of control intake for 5-6 consecutive days, and ad libitum intake for 1-3 days. Weight loss efficiency during this phase was calculated as (total weight change) ÷ [(total energy intake of mice on CD or ID)-(total average energy intake of controls)]. Subsets of mice then underwent a 3-week weight regain phase involving ad libitum re-feeding. RESULTS: Mice on the ID showed transient hyperphagia relative to controls during each 1-3-day ad libitum feeding period, and overall ate significantly more than CD mice (91.1±1.0 versus 82.2±0.5% of control intake respectively, n = 10, P<0.05). There were no significant differences between CD and ID groups at the end of the weight loss or weight regain phases with respect to body weight, fat mass, circulating glucose or insulin concentrations, or the insulin resistance index. Weight loss efficiency was significantly greater with ID than with CD (0.042±0.007 versus 0.018±0.001 g/kJ, n = 10, P<0.01). Mice on the CD exhibited significantly greater hypothalamic mRNA expression of proopiomelanocortin (POMC) relative to ID and control mice, with no differences in neuropeptide Y or agouti-related peptide mRNA expression between energy-restricted groups. CONCLUSION: Intermittent moderate energy restriction may offer an advantage over continuous moderate energy restriction, because it induces significantly greater weight loss relative to energy deficit in mice.

Pancreatic PYY Is Critical in the Control of Insulin Secretion and Glucose Homeostasis in Female Mice.

Insulin secretion is tightly controlled through coordinated actions of a number of systemic and local factors. Peptide YY (PYY) is expressed in α-cells of the islet, but its role in control of islet function such as insulin release is not clear. In this study, we generated a transgenic mouse model (Pyy(tg/+)/Rip-Cre) overexpressing the Pyy gene under the control of the rat insulin 2 gene promoter and assessed the impact of islet-released PYY on ß-cell function, insulin release, and glucose homeostasis in mice. Our results show that up-regulation of PYY in islet ß-cells leads to an increase in serum insulin levels as well as improved glucose tolerance. Interestingly, PYY-overproducing mice show increased lean mass and reduced fat mass with no significant changes in food intake or body weight. Energy expenditure is also increased accompanied by increased respiratory exchange ratio. Mechanistically, the enhanced insulin levels and improved glucose tolerance are primarily due to increased ß-cell mass and secretion. This is associated with alterations in the expression of genes important for ß-cell proliferation and function as well as the maintenance of the ß-cell phenotype. Taken together, these data demonstrate that pancreatic islet-derived PYY plays an important role in controlling glucose homeostasis through the modulation of ß-cell mass and function.

CART in the regulation of appetite and energy homeostasis.

The cocaine- and amphetamine-regulated transcript (CART) has been the subject of significant interest for over a decade. Work to decipher the detailed mechanism of CART function has been hampered by the lack of specific pharmacological tools like antagonists and the absence of a specific CART receptor(s). However, extensive research has been devoted to elucidate the role of the CART peptide and it is now evident that CART is a key neurotransmitter and hormone involved in the regulation of diverse biological processes, including food intake, maintenance of body weight, reward and addiction, stress response, psychostimulant effects and endocrine functions (Rogge et al., 2008; Subhedar et al., 2014). In this review, we focus on knowledge gained on CART's role in controlling appetite and energy homeostasis, and also address certain species differences between rodents and humans.

Stress- and diet-induced fat gain is controlled by NPY in catecholaminergic neurons.

Neuropeptide Y (NPY) and noradrenaline are commonly co-expressed in sympathetic neurons. Both are key regulators of energy homeostasis and critical for stress-coping. However, little is known about the specific function of NPY in the catecholaminergic system in these regulations. Here we show that mice with NPY expression only in the noradrenergic and adrenergic cells of the catecholaminergic system (catNPY) exhibited exacerbated diet-induced obesity, lower body and brown adipose tissue temperatures compared to WT and NPY(-/-) mice under a HFD. Furthermore, chronic stress increased adiposity and serum corticosterone level in WT but not NPY(-/-) mice. Re-introducing NPY specifically to the catecholaminergic system in catNPY mice restored stress responsiveness associated with increased respiratory exchange ratio and decreased liver pACC to tACC ratio. These results demonstrate catecholaminergic NPY signalling is critical in mediating diet- and chronic stress-induced fat gain via effects on diet-induced thermogenesis and stress-induced increases in corticosterone levels and lipogenic capacity.

Pancreatic polypeptide controls energy homeostasis via Npy6r signaling in the suprachiasmatic nucleus in mice.

Y-receptors control energy homeostasis, but the role of Npy6 receptors (Npy6r) is largely unknown. Young Npy6r-deficient (Npy6r(-/-)) mice have reduced body weight, lean mass, and adiposity, while older and high-fat-fed Npy6r(-/-) mice have low lean mass with increased adiposity. Npy6r(-/-) mice showed reduced hypothalamic growth hormone releasing hormone (Ghrh) expression and serum insulin-like growth factor-1 (IGF-1) levels relative to WT. This is likely due to impaired vasoactive intestinal peptide (VIP) signaling in the suprachiasmatic nucleus (SCN), where we found Npy6r coexpressed in VIP neurons. Peripheral administration of pancreatic polypeptide (PP) increased Fos expression in the SCN, increased energy expenditure, and reduced food intake in WT, but not Npy6r(-/-), mice. Moreover, intraperitoneal (i.p.) PP injection increased hypothalamic Ghrh mRNA expression and serum IGF-1 levels in WT, but not Npy6r(-/-), mice, an effect blocked by intracerebroventricular (i.c.v.) Vasoactive Intestinal Peptide (VPAC) receptors antagonism. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition.

PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice.

OBJECTIVE: Peptide YY (PYY3-36) and pancreatic polypeptide (PP) potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. DESIGN AND METHODS: Fasted WT, Y2(-) (/) (-) , Y4(-) (/) (-) , or Y2Y4(-) (/) (-) mice were i.p. administrated with saline, PYY3-36, and/or PP. RESULTS: Combined injection of PYY3-36 and PP reduces food intake in an additive manner was demonstrated in this study. This effect is mediated via Y2 and Y4 receptors, respectively. It was demonstrated that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the arcuate nucleus (Arc), paraventricular nucleus, and dorso-medial nucleus of the hypothalamus (DMH) are activated with minimal responses seen in the ventro-medial nucleus of the hypothalamus (VMH) and lateral hypothalamic area (LHA) of WT mice. These effects are absent in Y2(-) (/) (-) mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH, and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c-fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction. CONCLUSIONS: These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner.

Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN.

Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically, a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.

Peripheral-specific y2 receptor knockdown protects mice from high-fat diet-induced obesity.

Y2 receptors, particularly those in the brain, have been implicated in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone mass. Recent evidence also indicates a role for Y2 receptors in peripheral tissues in this process by promoting adipose tissue accretion; however their effects on energy balance remain unclear. Here, we show that adult-onset conditional knockdown of Y2 receptors predominantly in peripheral tissues results in protection against diet-induced obesity accompanied by significantly reduced weight gain, marked reduction in adiposity and improvements in glucose tolerance without any adverse effect on lean mass or bone. These changes occur in association with significant increases in energy expenditure, respiratory exchange ratio, and physical activity and despite concurrent hyperphagia. On a chow diet, knockdown of peripheral Y2 receptors results in increased respiratory exchange ratio and physical activity with no effect on lean or bone mass, but decreases energy expenditure without effecting body weight or food intake. These results suggest that peripheral Y2 receptor signaling is critical in the regulation of oxidative fuel selection and physical activity and protects against the diet-induced obesity. The lack of effects on bone mass seen in this model further indicates that bone mass is primarily controlled by non-peripheral Y2 receptors. This study provides evidence that novel drugs that target peripheral rather than central Y2 receptors could provide benefits for the treatment of obesity and glucose intolerance without adverse effects on lean and bone mass, with the additional benefit of avoiding side effects often associated with pharmaceuticals that act on the central nervous system.