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The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2–4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic–euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.

OBJECTIVE--To characterize the hormonal milieu and adipose gene expression in response to catch-up growth (CUG), a growth pattern associated with obesity and diabetes risk, in a mouse model of low birth weight (LBW). RESEARCH DESIGN AND METHODS--ICR mice were food restricted by 50% from gestational days 12.5-18.5, reducing offspring birth weight by 25%. During the suckling period, dams were either fed ad libitum, permitting CUG in offspring, or food restricted, preventing CUG. Offspring were killed at age 3 weeks, and gonadal fat was removed for RNA extraction, array analysis, RT-PCR, and evaluation of cell size and number. Serum insulin, thyroxine (T4), corticosterone, and adipokines were measured. RESULTS--At age 3 weeks, LBW mice with CUG (designated U-C) had body weight comparable with controls (designated C-C); weight was reduced by 49% in LBW mice without CUG (designated U-U). Adiposity was altered by postnatal nutrition, with gonadal fat increased by 50% in U-C and decreased by 58% in U-U mice (P < 0.05 vs. C-C mice). Adipose expression of the lipogenic genes Fasn, AccI, Lpin1, and Srebf1 was significantly increased in U-C compared with both C-C and U-U mice (P < 0.05). Mitochondrial DNA copy number was reduced by >50% in U-C versus U-U mice (P = 0.014). Although cell numbers did not differ, mean adipocyte diameter was increased in U-C and reduced in U-U mice (P < 0.01). CONCLUSIONS--CUG results in increased adipose tissue lipogenic gene expression and adipocyte diameter but not increased cellularity, suggesting that catch-up fat is primarily associated with lipogenesis rather than adipogenesis in this murine model., Low-birth weight (LBW) infants are at increased risk for hypertension, type 2 diabetes, and metabolic syndrome (1). Mechanisms remain ill defined but may involve epigenetic regulation of development and gene [...]

* Objective.--We determined if coffee consumption is associated with an increased risk of developing coronary heart disease. Data Identification.--Articles published between 1966 and August 1991 examining a possible link between coffee and coronary heart disease were identified by a computer-aided literature search (Medline) and by standard bibliographic searches. Study Selection.--All prospective cohort studies providing data on daily coffee consumption and coronary events (acute myocardial infarction and/or coronary death) were included. Data Extraction.--Data from each published article were extracted. Additional unpublished data augmenting those published for one study were also included. Each cohort was categorized by reported daily coffee consumption. Incidence of coronary events at each level of coffee consumption was the primary outcome. Results.--Eleven prospective studies were included. The coronary events for subjects consuming little or no coffee ([is less than or equal to] 1 cup per day) were compared with event rates for those consuming greater amounts of coffee. The studies exhibited heterogeneity of results. The typical odds ratios and 95% confidence intervals across studies were estimated by logistic regression analysis. Coffee intake from 1 to 4 cups per day was not associated with any increase in coronary heart disease occurrence compared with 1 cup or less per day (odds ratio, 1.01; confidence interval [0.93, 1.11]). The odds ratios for 4 to 6 and 6 cups or more per day compared with up to 1 cup per day were 1.01 (0.90, 1.12) and 1.09 (0.97, 1.22), respectively. Conclusions.--There is no association between coffee consumption and the occurrence of coronary heart disease. This conclusion holds in the absence of adjustment for other coronary risk factors. (Arch Intern Med. 1992;152:1767-1772)

Palpitations, the sensation of rapid, irregular of extra heartbeats, are often attributed to caffeine consumption. A review of the literature on the topic suggests that this is unsubstantiated by existing studies. One animal study demonstrated a reduction in the threshold for ventricular fibrillation, a dangerous type of arrhythmia, in dogs with acute myocardial infarction (heart attack) that are dosed with caffeine. However, the doses of caffeine were considerably higher than those generally ingested by humans. Another dog study showed no difference in ventricular fibrillation threshold in either caffeine or placebo fed dogs, but did show that adding five cigarettes a day (by tracheostomy) to the caffeine group lowered the ventricular fibrillation threshold. The effects of cigarettes alone were not studied. Human electrophysiologic studies suggest that caffeine does not affect the normal cardiac electric conduction system, but might aggravate preexisting rhythm disturbances. Another study of ventricular extrasystoles (isolated ectopic beats) with over 7,000 patients showed that those who consumed nine or more cups of coffee per day were twice as likely to experience ventricular extrasystole than those who drank three cups per day. However, it is unknown whether drinking more than nine cups per day is associated with a greater frequency of other coronary risk factors, such as smoking, obesity, and a sedentary lifestyle. Several studies of post-myocardial infarction patients showed no difference in the rate of cardiac arrhythmias in subjects given caffeine compared with those given placebo. In another study of patients with known ventricular irritability and malignant arrhythmias, caffeine was no more likely than placebo to induce those arrhythmias. Thus, moderate caffeine consumption has not been shown to increase the frequency of arrhythmias in normal subjects, patients with recent myocardial infarctions, or those with known ventricular arrhythmias. (Consumer Summary produced by Reliance Medical Information, Inc.)

Comparatively high doses of thiazide diuretics have been implicated as a possible cause of ventricular arrhythmias. With the advent of lower recommended dosages, the effect of hydrechlorothiazide 50 mg daily alone and in combination with the potassium-sparing drug, amiloride 5 mg, on the frequency and severity of ventricular arrhythmias was examined in 37 elderly patients. The mean age was 81 + 2 years. The study used a randomized, doubleblind, crossover design with 3 treatment phases: hydrochlorothiazide, hydrochlorothiazide + amiloride and placebo. A 24-hour Holter monitor recording and serum potassium measurement were obtained at the end of each treatment. Mean serum potassium was significantly (p (Am J Cardiol 1990;65:599-603), Diuretics, drugs which remove water from the body and increase urine secretion, are frequently used to treat high blood pressure and other cardiovascular conditions. Most diuretics also cause loss of potassium, an electrolyte which is important for maintenance of the normal electrical state of cells. Studies have varied as to whether diuretic-induced hypokalemia (low blood potassium) can lead to arrhythmias (abnormal heartbeat), related to altered electrical conduction. Some of the studies used elevated doses of diuretics to provoke hypokalemia. Older individuals are frequently treated with diuretics, and may be prone to arrhythmias in the absence of known heart disease. Thirty-seven patients over 75 years of age in chronic-care institutions were given a thiazide (a hypokalemic diuretic; 50 mg), a thiazide plus amiloride (a potassium-sparing diuretic; 5 mg), and a placebo, separately, for 2-week spans each. Continuous 24-hour Holter ECG (electrocardiogram) readings were made at the end of each treatment phase. There was little difference in occurrence of ventricular arrhythmias (VA) between placebo and thiazide, with 13 thiazide treatments resulting in serious VA, while 15 patients on placebo experienced this. In patients who had VA while receiving placebo, there was a trend toward an increase in arrhythmia while on thiazide, but this was not significant. Only nine patients had serious VA while receiving thiazide plus amiloride. Thiazide treatment caused serum potassium levels to be significantly lower than with other treatments. The study indicates that older patients receiving clinically appropriate doses of thiazide do not sustain important increases in VA occurrence. Further studies in younger individuals with and without a predilection for VA would be useful in clarifying this issue. (Consumer Summary produced by Reliance Medical Information, Inc.)

In the last three decades protocols for the validation of blood pressure measuring devices have been developed by the US Association for the Advancement of Medical Instrumentation, the British Hypertension Society, the German Hypertension League, the European Society of Hypertension Working Group on blood pressure Monitoring and the International Organization for Standardization. The European Society of Hypertension International Protocol required much smaller sample size than the other protocols, aiming to reduce the time, resources and cost of validation studies and thereby increase the number of validated devices. Given its specifications, the European Society of Hypertension International Protocol was adequate for ‘high- and low-accuracy’ devices, yet assessment of ‘moderate accuracy’ devices had high uncertainty with resultant high rate of device failure. Thus, devices validated using the European Society of Hypertension International Protocol should be considered to be as accurate as those validated with the previous Association for the Advancement of Medical Instrumentation or British Hypertension Society protocols. However, the European Society of Hypertension International Protocol did not allow subgroup evaluation (arm sizes, special populations, etc). The mission of the European Society of Hypertension International Protocol to promote the concept of validation has been well achieved, as almost double studies have been published using it than all the other protocols together. However, the maintenance of different validation protocols is confusing and therefore experts from the Association for the Advancement of Medical Instrumentation, European Society of Hypertension International Protocol and International Organization for Standardization have now developed the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) as the recommended 21st-century procedure for worldwide application. The European Society of Hypertension Working Group has published a practical guide for using the Universal Standard. It is in the interests of all scientific bodies to propagate the Universal Standard and ensure its wide implementation.

In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.

IMPORTANCE: Automated office blood pressure (AOBP) measurement involves recording several blood pressure (BP) readings using a fully automated oscillometric sphygmomanometer with the patient resting alone in a quiet place. Although several studies have shown AOBP measurement to be more accurate than routine office BP measurement and not subject to a “white coat effect,” the cumulative evidence has not yet been systematically reviewed. OBJECTIVE: To perform a systematic review and meta-analysis to examine the association between AOBP and office BP readings measured in routine clinical practice and in research studies, and ambulatory BP recorded during awake hours, as the latter is a standard for predicting future cardiovascular events. DATA SOURCES: The MEDLINE, Embase, and Cochrane Library were searched from 2003 to April 25, 2018. STUDY SELECTION: Studies on systolic and diastolic BP measurement by AOBP in comparison with awake ambulatory BP, routine office BP, and research BP measurements were included if they contained 30 patients or more. DATA EXTRACTION AND SYNTHESIS: Study characteristics were abstracted independently and random effects meta-analyses and meta-regressions were conducted. MAIN OUTCOMES AND MEASURES: Pooled mean differences (95% CI) of systolic and diastolic BP between types of BP measurement. RESULTS: Data were compiled from 31 articles comprising 9279 participants (4736 men and 4543 women). In samples with systolic AOBP of 130 mm Hg or more, routine office and research systolic BP readings were substantially higher than AOBP readings, with a pooled mean difference of 14.5 mm Hg (95% CI, 11.8-17.2 mm Hg; n = 9; I2 = 94.3%; P &lt; .001) for routine office systolic BP readings and 7.0 mm Hg (95% CI, 4.9-9.1 mm Hg; n = 9; I2 = 85.7%; P &lt; .001) for research systolic BP readings. Systolic awake ambulatory BP and AOBP readings were similar, with a pooled mean difference of 0.3 mm Hg (95% CI, −1.1 to 1.7 mm Hg; n = 19; I2 = 90%; P &lt; .001). CONCLUSIONS AND RELEVANCE: Automated office blood pressure readings, only when recorded properly with the patient sitting alone in a quiet place, are more accurate than office BP readings in routine clinical practice and are similar to awake ambulatory BP readings, with mean AOBP being devoid of any white coat effect. There has been some reluctance among physicians to adopt this technique because of uncertainty about its advantages compared with more traditional methods of recording BP during an office visit. Based on the evidence, AOBP should now be the preferred method for recording BP in routine clinical practice.

The central melanocortin system plays a crucial role in the control of energy balance. Although the decreased energy expenditure and increased adiposity of melanocortin-3 receptor (Mc3R)-null mice suggest the importance of Mc3R-regulated neurons in energy homeostasis, the roles for specific subsets of Mc3R neurons in energy balance have yet to be determined. Because the lateral hypothalamic area (LHA) contributes to the control of energy expenditure and feeding, we generated Mc3rcre mice to determine the roles of LHA Mc3R (Mc3RLHA) neurons in energy homeostasis. We found that Mc3RLHA neurons overlap extensively with LHA neuron markers that contribute to the control of energy balance (neurotensin, galanin, and leptin receptor) and project to brain areas involved in the control of feeding, locomotion, and energy expenditure, consistent with potential roles for Mc3RLHA neurons in these processes. Indeed, selective chemogenetic activation of Mc3RLHA neurons increased locomotor activity and augmented refeeding after a fast. Although the ablation of Mc3RLHA neurons did not alter food intake, mice lacking Mc3RLHA neurons displayed decreased energy expenditure and locomotor activity, along with increased body mass and adiposity. Thus, Mc3R neurons lie within LHA neurocircuitry that modulates locomotor activity and energy expenditure and contribute to energy balance control.

Summary points Two manual sphygmomanometers have been validated, one is recommended Five devices for clinical use in hospitals have been validated, two are recommended 23 devices for self measurement of [...]

We characterized metabolic and mitogenic signaling pathways in isolated skeletal muscle from well-matched type 2 diabetic and control subjects. Time course studies of the insulin receptor, insulin receptor substrate (IRS)-1/2, [...]

Diminished insulin action in the vasculature may contribute to the development of cardiovascular diseases in diabetes. We have studied insulin's effects on the phosphatidylinositol (PI) 3-kinase pathway in arterial smooth [...]

Autophosphorylation of the juxtamembrane [Tyr.sup.960] of the insulin receptor during insulin stimulation creates a binding site for the SH2 and PTB domains of insulin receptor substrates (including Shc and the [...]

IRS-proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, IGF-1 and various cytokines. We compared the functions of IRS-1, IRS-2 and IRS-4 in 32D [...]

Disruption of IRS1 in mice significantly retards growth (50-60%) but produces only mild insulin resistance. However, when IRS2 is disrupted, the animals are born with marked glucose intolerance upon birth [...]

The adipocyte-derived hormone, Leptin (Ob), regulates body energy balance via the leptin receptor (Ob R)-- a type I cytokine receptor. Although multiple alternately spliced isoforms of the leptin receptor exist, [...]

The adipocyte-derived hormone leptin acts via its receptor (LepRb) on central nervous system neurons to communicate the repletion of long-term energy stores, to decrease food intake, and to promote energy expenditure. We generated mice that express Cre recombinase from the calcitonin receptor (Calcr) locus (Calcrcremice) to study Calcr-expressing LepRb (LepRbCalcr) neurons, which reside predominantly in the arcuate nucleus (ARC). Calcrcre-mediated ablation of LepRb in LepRbCalcrknockout (KO) mice caused hyperphagic obesity. Because LepRb-mediated transcriptional control plays a crucial role in leptin action, we used translating ribosome affinity purification followed by RNA sequencing to define the transcriptome of hypothalamic Calcrneurons, along with its alteration in LepRbCalcrKO mice. We found that ARC LepRbCalcrcells include neuropeptide Y (NPY)/agouti-related peptide (AgRP)/?-aminobutyric acid (GABA) (“NAG”) cells as well as non-NAG cells that are distinct from pro-opiomelanocortin cells. Furthermore, although LepRbCalcrKO mice exhibited dysregulated expression of several genes involved in energy balance, neither the expression of Agrpand Npynor the activity of NAG cells was altered in vivo. Thus, although direct leptin action via LepRbCalcrcells plays an important role in leptin action, our data also suggest that leptin indirectly, as well as directly, regulates these cells.Leptin acts via calcitonin receptor?expressing hypothalamic neurons to control feeding and energy balance.

Growing evidence implicates neurons that project from the lateral parabrachial nucleus (LPBN) to the hypothalamic ventromedial nucleus (VMN) in a neurocircuit that drives counterregulatory responses to hypoglycemia, including increased glucagon secretion. Among LPBN neurons in this circuit is a subset that expresses cholecystokinin (LPBNCCKneurons) and is tonically inhibited by leptin. Because uncontrolled diabetes is associated with both leptin deficiency and hyperglucagonemia, and because intracerebroventricular (ICV) leptin administration reverses both hyperglycemia and hyperglucagonemia in this setting, we hypothesized that deficient leptin inhibition of LPBNCCKneurons drives activation of this LPBN?VMN circuit and thereby results in hyperglucagonemia. Here, we report that although bilateral microinjection of leptin into the LPBN does not ameliorate hyperglycemia in rats with streptozotocin-induced diabetes mellitus (STZ-DM), it does attenuate the associated hyperglucagonemia and ketosis. To determine if LPBN leptin signaling is required for the antidiabetic effect of ICV leptin in STZ-DM, we studied mice in which the leptin receptor was selectively deleted from LPBNCCKneurons. Our findings show that although leptin signaling in these neurons is not required for the potent antidiabetic effect of ICV leptin, it is required for leptin-mediated suppression of diabetic hyperglucagonemia. Taken together, these findings suggest that leptin-mediated effects in animals with uncontrolled diabetes occur through actions involving multiple brain areas, including the LPBN, where leptin acts specifically to inhibit glucagon secretion and associated ketosis.In uncontrolled diabetes, deficient leptin action in the lateral parabrachial nucleus contributes to increased glucagon levels and associated ketosis in this setting.

Obesity represents the single most important risk factor for early disability and death in developed societies, and the incidence of obesity remains at staggering levels. CNS systems that modulate energy intake and expenditure in response to changes in body energy stores serve to maintain constant body adiposity; the adipocyte-derived hormone leptin and its receptor (LEPR) represent crucial regulators of these systems. As in the case of insulin resistance, a variety of mechanisms (including feedback inhibition, inflammation, gliosis and endoplasmic reticulum stress) have been proposed to interfere with leptin action and impede the systems that control body energy homeostasis to promote or maintain obesity, although the relative importance and contribution of each of these remain unclear. However, LEPR signalling may be increased (rather than impaired) in common obesity, suggesting that any obesity-associated defects in leptin action must result from lesions somewhere other than the initial LEPR signal. It is also possible that increased LEPR signalling could mediate some of the obesity-associated changes in hypothalamic function.

Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2-3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients.

Obesity is primarily due to food intake in excess of the body’s energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT2CR) is a target for the treatment of human obesity. Mechanistically, 5-HT2CRs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT2CRs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT2CR agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT2CR expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT2CR expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT2CRCREline to clarify the function of subset of 5-HT2Creceptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2Creceptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT2Creceptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT2CR neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

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Human variants of the adapter protein SH2B1 are associated with severe childhood obesity, hyperphagia, and insulin resistance—phenotypes mimicked by mice lacking Sh2b1. SH2B1β and γ isoforms are expressed ubiquitously, whereas SH2B1α and δ isoforms are expressed primarily in the brain. Restoring SH2B1β driven by the neuron-specific enolase promoter largely reverses the metabolic phenotype of Sh2b1-null mice, suggesting crucial roles for neuronal SH2B1β in energy balance control. Here we test this hypothesis by using CRISPR/Cas9 gene editing to delete the β and γ isoforms from the neurons of mice (SH2B1βγ neuron-specific knockout [NKO] mice) or throughout the body (SH2B1βγ knockout [KO] mice). While parameters of energy balance were normal in both male and female SH2B1βγ NKO mice, food intake, body weight, and adiposity were increased in male (but not female) SH2B1βγ KO mice. Analysis of long-read single-cell RNA seq data from wild-type mouse brain revealed that neurons express almost exclusively the α and δ isoforms, whereas neuroglial cells express almost exclusively the β and γ isoforms. Our work suggests that neuronal SH2B1β and γ are not primary regulators of energy balance. Rather, non-neuronal SH2B1β and γ in combination with neuronal SH2B1α and δ suffice for body weight maintenance. While SH2B1β/γ and SH2B1α/δ share some functionality, SH2B1β/γ appears to play a larger role in promoting leanness.

Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.

Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues before ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the preconsummatory modulation of ARCAgRPneurons. In a manner reciprocal to ARCAgRPneurons, ARC-projecting leptin receptor-expressing GABAergic vDMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, leptin receptor-expressing GABAergic vDMH neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRPneuron activity and feeding behavior.

A variety of data suggest that estrogen action on kisspeptin (Kiss1)-containing arcuate nucleus neurons (which coexpress Kiss1, neurokinin B (the product of Tac2) and dynorphin (KNDy) neurons restrains reproductive onset and function, but roles for estrogen action in these Kiss1 neurons relative to a distinct population of rostral hypothalamic Kiss1 neurons (which does not express Tac2 or dynorphin) have not been directly tested. To test the role for estrogen receptor (ER)α in KNDy cells, we thus generated Tac2Creand Kiss1Creknock-in mice and bred them onto the Esr1floxbackground to ablate ERα specifically in Tac2-expressing cells (ERαTac2KOmice) or all Kiss1cells (ERαKiss1KOmice), respectively. Most ERα-expressing Tac2neurons represent KNDy cells. Arcuate nucleus Kiss1expression was elevated in ERαTac2KOand ERαKiss1KOfemales independent of gonadal hormones, whereas rostral hypothalamic Kiss1expression was normal in ERαTac2KObut decreased in ERαKiss1KOfemales; this suggests that ERα in rostral Kiss1cells is crucial for control of Kiss1expression in these cells. Both ERαKiss1KOand ERαTac2KOfemales displayed early vaginal opening, early and persistent vaginal cornification, increased gonadotropins, uterine hypertrophy, and other evidence of estrogen excess. Thus, deletion of ERα in Tac2neurons suffices to drive precocious gonadal hyperstimulation, demonstrating that ERα in Tac2neurons typically restrains pubertal onset and hypothalamic reproductive drive.

Leptin is an adipocytokine that circulates in proportion to body fat to signal the repletion of long-term energy stores. Leptin acts via its receptor, LepRb, on specialized neuronal populations in the brain (mainly in the hypothalamus and brainstem) to alter motivation and satiety, as well as to permit energy expenditure and appropriate glucose homeostasis. Decreased leptin, as with prolonged caloric restriction, promotes a powerful orexigenic signal, decreases energy use via a number of neuroendocrine and autonomic axes, and disrupts glucose homeostasis. Here, we review what is known about cellular leptin action and focus on the roles for specific populations of LepRb-expressing neurons for leptin action.

During the past few decades, biomedical researchers have studied caffeine more intensively than almost any other substance, naturally occurring or synthetic. Yet, when all the data have been analyzed, caffeine [...]

Measurement of office blood pressure using a fully automated sphygmomanometer that takes multiple readings with the patient resting quietly alone has been called automated office blood pressure (AOBP). Almost all AOBP research has involved the patient resting alone in an examining room, which is often impractical in a clinical setting. The possibility that valid AOBP readings can be obtained with the patient resting quietly in a waiting room was examined.

Unlike mammals, zebrafish can regenerate a damaged retina. This remarkable regenerative response is mediated by Müller glia (MG) that undergo a reprogramming event that drives their proliferation and the generation of multipotent progenitors for retinal repair. The mechanisms that drive MG reprogramming are poorly understood. Here, we report that Leptin and Gp130-coupled receptors, acting via a Jak/Stat signaling pathway, stimulate MG reprogramming and progenitor formation in the injured retina. Importantly, we find that ascl1agene expression, which drives MG reprogramming in fish and mammals, is regulated in a Jak/Stat-dependent manner and requires consensus Stat-binding sites for injury-dependent activation. Finally, we identify cytokines that are induced by retinal injury and exhibit a remarkable synergy in their ability to activate Jak/Stat signaling and MG reprogramming in the uninjured retina. Our study not only furthers our understanding of retina regeneration in zebrafish but also suggests new strategies for awakening retina regeneration in mammals.

To determine the prevalence of masked hypertension normal office blood pressure (BP) with high awake ambulatory BP using automated office BP (AOBP) or conventional manual office BP (MOBP) measurement in routine clinical practice.

Clinical practice guidelines have traditionally recommended manual blood pressure (BP) measurement in the office setting as the standard method for diagnosing hypertension. In reality, manual BP in routine clinical practice is relatively inaccurate, over-diagnoses hypertension by provoking office-induced increases in BP and correlates poorly with both the awake ambulatory BP and target organ damage. The most recent guidelines recommend 24-h ambulatory BP and home BP for diagnosing hypertension. The advent of automated office BP (AOBP) represents a third alternative to conventional manual BP measurement, one that maintains the role of office BP readings in the diagnosis and management of hypertension. AOBP has three basic principles: multiple readingstaken using a fully automatedsphygmomanometer with the patient resting quietly alone. AOBP eliminates office-induced hypertension such that the cut-point for a normal AOBP is the same as for the awake ambulatory BP and home BP. As compared to routine manual office BP, AOBP provides more accurate BP readings, is more consistent during repeated office visits and in different settings and correlates better with both the awake ambulatory BP and target organ damage. The advantages of AOBP over manual BP measurement support its use in routine clinical practice.

Manual blood pressure (BP) is gradually disappearing from clinical practice with the mercury sphygmomanometer now considered to be an environmental hazard. Manual BP is also subject to measurement error on the part of the physician/nurse and patient-related anxiety which can result in poor quality BP measurements and office-induced (white coat) hypertension. Automated office (AO) BP with devices such as the BpTRU (BpTRU Medical Devices, Coquitlam, BC) has already replaced conventional manual BP in many primary care practices in Canada and has also attracted interest in other countries where research studies using AOBP have been undertaken. The basic principles of AOBP include multiple readings taken with a fully automated recorder with the patient resting alone in a quiet room. When these principles are followed, office-induced hypertension is eliminated and AOBP exhibits a much stronger correlation with the awake ambulatory BP as compared with routine manual BP measurements. Unlike routine manual BP, AOBP correlates as well with left ventricular mass as does the awake ambulatory BP. AOBP also simplifies the definition of hypertension in that the cut point for a normal AOBP (< 135/85 mm Hg) is the same as for the awake ambulatory BP and home BP. This article summarizes the currently available evidence supporting the use of AOBP in routine clinical practice and proposes an algorithm in which AOBP replaces manual BP for the diagnosis and management of hypertension.

To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension.

To validate an algorithm for the interpretation of automated office blood pressure (AOBP) measurement based upon data from untreated patients referred by physicians in the community for 24-h ambulatory blood pressure monitoring (ABPM).

To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension.

Leptin‐deficient ob/obmice are resistant to dextran sulfate sodium (DSS)‐induced colitis and Concanavalin A (Con A)‐induced hepatitis. However, the signal transduction pathways involved have not been identified. The present study investigated the effect of leptin‐induced STAT3 signaling in the DSS and Con A models. Mice carrying a leptin receptor (LEPR) gene mutant for Y1138 (s/smice), with abrogated leptin‐induced STAT3 signaling, were compared with wild‐type (WT) and LEPR‐deficient db/dbmice. Administration of DSS to s/smice resulted in a clinical score and colon shortening of intermediate severity compared with disease induced in WT and db/dbmice—the latter group having the lowest disease severity. A comparable degree of inflammatory infiltrate and epithelial damage was observed in the colon of WT and s/smice, and these parameters were reduced in db/dbmice. Levels of IFN‐γ, IL‐6, IL‐10, and TNF‐α were comparable in the colon of s/sand db/dbmice, and a similar trend was observed for CXCL2. s/sand WT mice developed severe liver disease in response to Con A, whereas db/dbmice were protected. However, Con A‐induced serum IL‐6 and TNF‐α levels in s/smice mimicked levels observed in db/dbrather than WT mice. In conclusion, lack of leptin‐induced STAT3 signaling is associated with reduced cytokine production following DSS and Con A administration, but it appears to sensitize mice to the effects of proinflammatory mediators.

To examine the possibility of reducing the white coat response using an automated sphygmomanometer designed for office use, the BpTRU. Consecutive patients referred from physicians in the community to an ambulatory blood pressure (ABP) monitoring unit in an academic hospital were included in the study.

To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension.

To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension.

AbstractThe increasing incidence of obesity in developed nations represents an ever-growing challenge to health care by promoting diabetes and other diseases. The discovery of the hormone, leptin, a decade ago has facilitated the acquisition of new knowledge regarding the regulation of energy balance. A great deal remains to be discovered regarding the molecular and anatomic actions of leptin, however. Here, we discuss the mechanisms by which leptin activates intracellular signals, the roles that these signals play in leptin action in vivo, and sites of leptin action in vivo. Using “reporter” mice, in which LRb-expressing (long form of the leptin receptor) neurons express the histological marker, β-galactosidase, coupled with the detection of LRb-mediated signal transducer and activator of transcription 3 signaling events, we identified LRb expression in neuronal populations both within and outside the hypothalamus. Understanding the regulation and physiological function of these myriad sites of central leptin action will be a crucial next step in the quest to understand mechanisms of leptin action and energy balance.

A patient has masked hypertension when his office blood pressure is less than 140/90mmHg but his ambulatory or home blood pressure readings are in the hypertensive range. Several recent studies have demonstrated that cardiovascular risk is similar between those with masked hypertension and those with sustained hypertension. The prevalence of masked hypertension in Canada is not known, but data from other countries suggest rates greater than 8%. Physicians need to use careful clinical judgment to identify and treat subjects with masked hypertension. The present review discusses masked hypertension, its importance to clinical practice and some aspects of patient management

To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with high blood pressure.

Leptin signals the status of body energy stores via the leptin receptor (LR), a member of the Type I cytokine receptor family. Type I cytokine receptors mediate intracellular signaling via the activation of associated Jak family tyrosine kinases. Although their COOH-terminal sequences vary, alternatively spliced LR isoforms (LRa-LRd) share common NH(2)-terminal sequences, including the first 29 intracellular amino acids. The so-called long form LR (LRb) activates Jak-dependent signaling and is required for the physiologic actions of leptin. In this study, we have analyzed Jak activation by intracellular LR sequences under the control of the extracellular erythropoeitin (Epo) (Epo receptor/LRb chimeras). We show that Jak2 is the requisite Jak kinase for signaling by the LRb intracellular domain and confirm the requirement for the Box 1 motif for Jak2 activation. A minimal LRb intracellular domain for Jak2 activation includes intracellular amino acids 31-48. Although the sequence requirements for intracellular amino acids 37-48 are flexible, intracellular amino acids 31-36 of LRb play a critical role in Jak2 activation and contain a loose homology motif found in other Jak2-activating cytokine receptors. The failure of short form sequences to function in Jak2 activation reflects the absence of this motif.