Implementation and Adaptation of the Safewards Model in the New Zealand Context. Perspectives of Tangata Whai Ora and Staff.

The safety of service users and staff is paramount in cultivating a therapeutic environment within inpatient mental health units. The Safewards model, originating in the United Kingdom, aims to reduce conflict and containment rates through 10 interventions. This study used participatory action research to explore the perspective of tangata whai ora and staff regarding the adaptation of the Safewards model to the unique New Zealand context. Such adaptation is critical due to significant health outcome disparities between Maori and non-Maori populations and the disproportionate representation of Maori within mental health services. In adhering to the principles of Te Tiriti o Waitangi, cultural adaptation becomes an imperative obligation. The study utilised qualitative content analysis and thematic analysis, drawing data from focus groups of staff (n = 15) and tangata whai ora (n = 3). This study describes a New Zealand Safewards model, which must include Te Ao Maori, align with current practices, adapt Safewards interventions and gain acceptance. Organisational change management is pivotal in the integration of this model into nursing practice. The outcomes of this study hold the potential to contribute to the formulation and implementation of a New Zealand Safewards model, while also bearing relevance for the international adaptation of Safewards to culturally diverse countries and healthcare systems.

Ocular and orbital manifestations of granulomatosis with polyangiitis: a systematic review of published cases.

Objective: Granulomatosis with polyangiitis (GPA) is an autoimmune disorder characterized by necrotizing granulomatous inflammation of small and medium-sized vessels. This systematic review aimed to highlight the most common ophthalmic manifestations and to uncover their associations with antineutrophil cytoplasmic antibody (ANCA) positivity and the presence of granulomas. Methods: A literature search of PubMed, Web of Science, and Scopus electronic databases was performed from journal inception to March 21, 2021, for case reports and a series of ophthalmic GPAs. Cytoplasmic-ANCA (c-ANCA), perinuclear-ANCA (p-ANCA), and granulomas were analyzed against many ophthalmic signs and symptoms. 306 patients with GPA were retrospectively studied. Results: Granulomas were present in 47.7% of our sample, c-ANCA in 59.2%, and p-ANCA in 10.8%. Scleritis was significantly associated with higher odds for c-ANCA positivity. Eye discharge, episcleritis, proptosis, and central nervous system (CNS) involvement were each significantly associated with lower odds for c-ANCA positivity. Orbital mass was significantly associated with lower odds for p-ANCA positivity. CNS involvement was significantly associated with higher odds for p-ANCA positivity (OR:3.08, 95% CI:1.02, 9.36, p=0.047) and orbital mass was significantly associated with lower odds for p-ANCA positivity. Conclusions: We recommend that clinicians should consider ocular or orbital GPA in patients presenting with non-specific eye complaints, such as vision impairment, orbital mass, or proptosis, and obtain further assessments to determine the possible presence of granuloma, c-ANCA, or p-ANCA. Abbreviations: GPA = Granulomatosis with Polyangiitis, ANCA = antineutrophil cytoplasmic antibody, c-ANCA = cytoplasmic-ANCA, p-ANCA = perinuclear-ANCA, CNS = central nervous system, AAVs = ANCA-associated vasculitides, SD = standard deviation, GU = genitourinary, ENT = ear nose and throat, OR = odds ratio, CI = confidence interval.

An analysis of the barriers and enablers to implementing the Safewards model within inpatient mental health services.

Mental health inpatient units can provide a sanctuary for people to recover from mental illness. To support a therapeutic environment, the safety and well-being of service users and staff need protection through reduced conflict and containment rates. The Safewards model identifies 10 interventions to prevent conflict and containment. This paper aims to present barriers and enablers to implementing Safewards by analysing current literature on the Safewards model. It will also compare the Safewards model to New Zealand's Six Core Strategies. In a systematic search of 12 electronic databases following the PRISMA flow chart, 22 primary studies were included in this analysis. JBI tools were used for quality appraisal and deductive content analysis was used to organize and interpret data. Four categories were identified: (a) designing the Safewards interventions and implementation; (b) staff participation and perception of Safewards; (c) healthcare system influences on Safewards implementation; (d) service user participation and perception of Safewards. To support successful Safewards implementation in future practice, this review recommends that Safewards implementation is enabled through robust design of the Safewards interventions and implementation methods; staff participation and positive perception of the Safewards model; a resourced healthcare system that prioritizes Safewards implementation; service user awareness and participation in Safewards interventions. Interactionist perspectives may support the implementation of Safewards. This analysis is limited by research settings mostly being inpatient adult services and inadequate capturing of the service user voice. An ongoing review of barriers and enablers is important for supporting future Safewards implementation.

Deprescribing in type 2 diabetes and cardiovascular disease: Recommendations for safe and effective initiation of glucagon-like peptide-1 receptor agonists in patients on insulin therapy.

Select glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular benefits in both primary and secondary prevention populations and are recommended in multiple guidelines for cardiovascular risk reduction in people with type 2 diabetes (T2D). Despite this, uptake of GLP-1 receptor agonists in clinical practice has been lagging. While the etiology of their underuse is multifactorial, lack of comfortability in adding a GLP-1 receptor agonist to established insulin regimens is a common barrier. Adjustments to basal and bolus insulin doses upon initiation of GLP-1 receptor agonists in trials have varied. When recommending empiric dose adjustments during initiation of GLP-1 receptors agonists, the most recent A1C and the current blood glucose levels, if available, should be taken into consideration. When initiating in a person being managed with basal-only insulin regimens, an empiric 20 % dose reduction is recommended if the baseline A1C is ≤8 %. For individuals using intensive insulin regimens, empiric dose reductions of up to 25 % in basal and 50 % in bolus therapy were implemented and summarized further in this review. Overall, initiation of GLP-1 receptor agonists can decrease insulin requirements and may permit deintensification of antihyperglycemic therapy through the reduction or discontinuation of bolus insulin therapy. As a result, this simplified regimen promotes increased adherence, reduces glycemic variability and hypoglycemia, and improves overall glycemic management and quality of life. This review aims to serve as a guide for clinicians to facilitate the initiation of GLP-1 receptor agonists and deintensification of insulin by providing suggested dose adjustments based on available literature.

The effects of anxiety, depressive, and obsessive-compulsive subclinical symptoms on performance monitoring.

Dysfunctional performance monitoring has been proposed as a potential neurocognitive biomarker of various internalising psychopathological symptoms, such as anxiety, depressive, and obsessive-compulsive symptoms. Given the overlapping neurophysiological findings and high rates of comorbidity amongst these internalising symptoms, an important research gap pertains to the specificity of performance monitoring to each of these symptoms. The aim of the present study was to examine the effects of anxiety, depressive, and obsessive-compulsive symptoms on performance monitoring in healthy adults. The sample consisted of 50 participants, with ages ranging from 18 to 33 years (M = 22.82, SD = 3.84). The Depression, Anxiety, and Stress Scales-21 and the Obsessive Compulsive Inventory-Revised were administered to assess the various internalising symptoms. An arrow flanker task was administered to elicit error responses whilst electrophysiological data were recorded from the scalp. Performance monitoring was indexed by the error-related negativity and correct response negativity. Bivariate correlations revealed that the three internalising symptoms were not associated with error-related negativity or correct response negativity amplitudes. However, a regression model revealed that greater levels of anxiety symptoms were uniquely associated with larger error-related negativity amplitude after controlling for depressive symptoms. In addition, greater levels of depressive symptoms were uniquely associated with smaller error-related negativity amplitude. Another regression model revealed that greater levels of depressive symptoms were uniquely associated with smaller correct response negativity amplitude after controlling for anxiety symptoms. These findings suggest that performance monitoring differentially associates with anxiety and depressive symptoms amongst healthy adults, providing some evidence of specificity for each respective symptoms.

Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance.

Understanding the neural components modulating feeding-related behavior and energy expenditure is crucial to combating obesity and its comorbidities. Neurons within the paraventricular nucleus of the hypothalamus (PVH) are a key component of the satiety response; activation of the PVH decreases feeding and increases energy expenditure, thereby promoting negative energy balance. In contrast, PVH ablation or silencing in both rodents and humans leads to substantial obesity. Recent studies have identified genetically-defined PVH subpopulations that control discrete aspects of energy balance (e.g. oxytocin (OXT), neuronal nitric oxide synthase 1 (NOS1), melanocortin 4-receptor (MC4R), prodynorphin (PDYN)). We previously demonstrated that non-OXT NOS1PVH neurons contribute to PVH-mediated feeding suppression. Here, we identify and characterize a non-OXT, non-NOS1 subpopulation of PVH and peri-PVH neurons expressing insulin-receptor substrate 4 (IRS4PVH) involved in energy balance control. Using Cre-dependent viral tools to activate, trace and silence these neurons, we highlight the sufficiency and necessity of IRS4PVH neurons in normal feeding and energy expenditure regulation. Furthermore, we demonstrate that IRS4PVH neurons lie within a complex hypothalamic circuitry that engages distinct hindbrain regions and is innervated by discrete upstream hypothalamic sites. Overall, we reveal a requisite role for IRS4PVH neurons in PVH-mediated energy balance which raises the possibility of developing novel approaches targeting IRS4PVH neurons for anti-obesity therapies.

Identification of the leptin receptor sequences crucial for the STAT3-Independent control of metabolism.

BACKGROUND: Leptin acts via its receptor, LepRb, on specialized neurons in the brain to modulate energy balance and glucose homeostasis. LepRb→STAT3 signaling plays a crucial role in leptin action, but LepRb also mediates an additional as-yet-unidentified signal (Signal 2) that is important for leptin action. Signal 2 requires LepRb regions in addition to those required for JAK2 activation but operates independently of STAT3 and LepRb phosphorylation sites. METHODS: To identify LepRb sequences that mediate Signal 2, we used CRISPR/Cas9 to generate five novel mouse lines containing COOH-terminal truncation mutants of LepRb. We analyzed the metabolic phenotype and measures of hypothalamic function for these mouse lines. RESULTS: We found that deletion of LepRb sequences between residues 921 and 960 dramatically worsens metabolic control and alters hypothalamic function relative to smaller truncations. We also found that deletion of the regions including residues 1013-1053 and 960-1013 each decreased obesity compared to deletions that included additional COOH-terminal residues. CONCLUSIONS: LepRb sequences between residues 921 and 960 mediate the STAT3 and LepRb phosphorylation-independent second signal that contributes to the control of energy balance and metabolism by leptin/LepRb. In addition to confirming the inhibitory role of the region (residues 961-1013) containing Tyr985, we also identified the region containing residues 1013-1053 (which contains no Tyr residues) as a second potential mediator of LepRb inhibition. Thus, the intracellular domain of LepRb mediates multiple Tyr-independent signals.

Transcriptional and physiological roles for STAT proteins in leptin action.

OBJECTIVES: Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression. METHODS: Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3LepRbKO mice), revealing the STAT3-dependent transcriptional targets of leptin. To understand roles for STAT proteins in leptin action, we also ablated STAT1 or STAT5 from LepRb neurons and expressed a constitutively-active STAT3 (CASTAT3) in LepRb neurons. RESULTS: While we also found increased Stat1 expression and STAT1-mediated transcription of leptin-regulated genes in Stat3LepRbKO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3LepRbKO background); ablating Stat5 in LepRb neurons also failed to alter energy balance. Importantly, expression of a constitutively-active STAT3 (CASTAT3) in LepRb neurons decreased food intake and body weight and improved metabolic parameters in leptin-deficient (ob/ob) mice, as well as in wild-type animals. CONCLUSIONS: Thus, STAT3 represents the unique STAT protein required for leptin action and STAT3 suffices to mediate important components of leptin action in the absence of other LepRb signals.

Specific subpopulations of hypothalamic leptin receptor-expressing neurons mediate the effects of early developmental leptin receptor deletion on energy balance.

OBJECTIVE: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons (e.g., arcuate nucleus (ARC) Pomc- or Agrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolic dysfunction. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance. METHODS: We generated new mouse lines deleted for LepRb in ARC GhrhCre neurons or in Htr2cCre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells. RESULTS: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc, Agrp, Ghrh, or Htr2c neurons minimally altered energy balance. CONCLUSIONS: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH.

Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action.

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.

Essential Role for Hypothalamic Calcitonin Receptor‒Expressing Neurons in the Control of Food Intake by Leptin.

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 (Calcrcre mice) 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 Calcr neurons, along with its alteration in LepRbCalcrKO mice. We found that ARC LepRbCalcr cells include neuropeptide Y (NPY)/agouti-related peptide (AgRP)/γ-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 Agrp and Npy nor the activity of NAG cells was altered in vivo. Thus, although direct leptin action via LepRbCalcr cells plays an important role in leptin action, our data also suggest that leptin indirectly, as well as directly, regulates these cells.

A leptin-regulated circuit controls glucose mobilization during noxious stimuli.

Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor-expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores.

Use of thromboelastography in the management of liver cirrhosis and accelerated intravascular coagulation and fibrinolysis (AICF).

In the presented case, the authors describe an obese middle-aged man that presented to the emergency department for persistent oedema, scleral icterus and fatigue. He was admitted to the hospital and diagnosed with liver cirrhosis via transjugular liver biopsy. He continued to bleed from the biopsy site for 5 days from accelerated intravascular coagulation and fibrinolysis (AICF) requiring multiple transfusions of packed red blood cells, fresh-frozen plasma and cryoprecipitate. The authors then used thromboelastography (TEG) to further characterise the patient's coagulopathy, which revealed platelet inhibition. The results of the TEG significantly changed future transfusion management. Finally, the authors conducted a literature review to summarise the current literature available for the use of TEG in the management of liver cirrhosis with AICF.

Functional identification of a neurocircuit regulating blood glucose.

Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN(SF1) neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN(SF1) neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN(SF1) fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN(SF1) neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN(SF1) neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN(SF1) neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMN(SF1)→aBNST neurocircuit.

ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice.

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 Tac2(Cre) and Kiss1(Cre) knock-in mice and bred them onto the Esr1(flox) background to ablate ERα specifically in Tac2-expressing cells (ERα(Tac2)KO mice) or all Kiss1 cells (ERα(Kiss1)KO mice), respectively. Most ERα-expressing Tac2 neurons represent KNDy cells. Arcuate nucleus Kiss1 expression was elevated in ERα(Tac2)KO and ERα(Kiss1)KO females independent of gonadal hormones, whereas rostral hypothalamic Kiss1 expression was normal in ERα(Tac2)KO but decreased in ERα(Kiss1)KO females; this suggests that ERα in rostral Kiss1 cells is crucial for control of Kiss1 expression in these cells. Both ERα(Kiss1)KO and ERα(Tac2)KO females displayed early vaginal opening, early and persistent vaginal cornification, increased gonadotropins, uterine hypertrophy, and other evidence of estrogen excess. Thus, deletion of ERα in Tac2 neurons suffices to drive precocious gonadal hyperstimulation, demonstrating that ERα in Tac2 neurons typically restrains pubertal onset and hypothalamic reproductive drive.

TRAP-seq defines markers for novel populations of hypothalamic and brainstem LepRb neurons.

OBJECTIVE: Leptin acts via its receptor (LepRb) on multiple subpopulations of LepRb neurons in the brain, each of which controls specific aspects of energy balance. Despite the importance of LepRb-containing neurons, the transcriptome and molecular identity of many LepRb subpopulations remain undefined due to the difficulty of studying the small fraction of total cells represented by LepRb neurons in heterogeneous brain regions. Here we sought to examine the transcriptome of LepRb neurons directly and identify markers for functionally relevant LepRb subsets. METHODS: We isolated mRNA from mouse hypothalamic and brainstem LepRb cells by Translating Ribosome Affinity Purification (TRAP) and analyzed it by RNA-seq (TRAP-seq). RESULTS: TRAP mRNA from LepRb cells was enriched for markers of peptidergic neurons, while TRAP-depleted mRNA from non-LepRb cells was enriched for markers of glial and immune cells. Genes encoding secreted proteins that were enriched in hypothalamic and brainstem TRAP mRNA revealed subpopulations of LepRb neurons that contained neuropeptide-encoding genes (including prodynorphin, Pdyn) not previously used as functional markers for LepRb neurons. Furthermore, Pdyn (cre) -mediated ablation of Lepr (flox) in Pdyn-expressing neurons (LepRb (Pdyn) KO mice) blunted energy expenditure to promote obesity during high-fat feeding. CONCLUSIONS: TRAP-seq of CNS LepRb neurons defines the LepRb neuron transcriptome and reveals novel markers for previously unrecognized subpopulations of LepRb neurons.

Ventral tegmental area neurotensin signaling links the lateral hypothalamus to locomotor activity and striatal dopamine efflux in male mice.

Projections from the lateral hypothalamic area (LHA) innervate components of the mesolimbic dopamine (MLDA) system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), to modulate motivation appropriately for physiologic state. Neurotensin (NT)-containing LHA neurons respond to multiple homeostatic challenges and project to the VTA, suggesting that these neurons could link such signals to MLDA function. Indeed, we found that pharmacogenetic activation of LHA NT neurons promoted prolonged DA-dependent locomotor activity and NAc DA efflux, suggesting the importance of VTA neurotransmitter release by LHA NT neurons for the control of MLDA function. Using a microdialysis-mass spectrometry technique that we developed to detect endogenous NT in extracellular fluid in the mouse brain, we found that activation of LHA NT cells acutely increased the extracellular concentration of NT (a known activator of VTA DA cells) in the VTA. In contrast to the prolonged elevation of extracellular NAc DA, however, VTA NT concentrations rapidly returned to baseline. Intra-VTA infusion of NT receptor antagonist abrogated the ability of LHA NT cells to increase extracellular DA in the NAc, demonstrating that VTA NT promotes NAc DA release. Thus, transient LHA-derived NT release in the VTA couples LHA signaling to prolonged changes in DA efflux and MLDA function.

20 years of leptin: connecting leptin signaling to biological function.

Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling proteins and protein tyrosine phosphatases also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models that have been used to elucidate these functions in vivo.

The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.

Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.

Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex.

Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre(+) Pten(flox/flox) mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip(+) neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.