Barriers to healthcare professionals recognizing and managing delirium in older adults during a hospital stay: A mixed-methods systematic review.

AIM: To investigate barriers to healthcare professionals recognizing and managing delirium in hospitalized older people. DESIGN: A mixed-methods systematic review. PROSPERO ID: CRD42020187932. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and CINAHL were searched (2007 to February 2023). REVIEW METHODS: Included studies focused on healthcare professionals' recognition and management of delirium for patients aged 65 years and over in a hospital ward or emergency department. Enhancing rigour, screening of results was conducted independently by two researchers. Qualitative and quantitative data were tabulated separately and grouped. Data were compared to identify similarities and differences. All studies were quality appraised. RESULTS: 43 studies were included; 24 quantitative, 16 qualitative and three mixed-methods. Data synthesis highlighted synergy between qualitative and quantitative findings. Barriers were reflected in six themes: (1) healthcare professionals' knowledge and understanding; (2) communication; (3) workforce development; (4) interprofessional working; (5) confounders; and (6) organizational constraints. CONCLUSIONS: Of significance, for older adults in hospital experiencing delirium, there is variability in whether and how well it is recognized and managed. To prevent adverse outcomes best practice guidance for screening, recognizing, diagnosing and managing delirium in older people needs to be agreed and disseminated widely. Supporting healthcare professionals to care for this patient population using an integrated approach is essential, how to involve and communicate with patients and their family and friends, how to recognize and manage delirium for patients with additional needs, e.g., those living with dementia and/or a learning disability. Hospitals need to have policy and guidance in place for the recognition and management of delirium in older adults presenting to a ward or to an emergency department. An IT infrastructure is needed that integrates assessments and care management plans in patient electronic records and makes them accessible within and across teams in hospital, primary and community care settings. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution to this systematic review. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Healthcare professionals can be better supported to be able to recognize and manage delirium during an acute hospital stay for older adults. This includes maximizing best care for those patients living with dementia, involving families and friends to help understand patients' baseline status and changes and supporting families and friends during this process. Of significance, attention to hospital IT infrastructures is warranted, integrating screening, assessment and care management plans in patients' electronic records and making these accessible to healthcare professionals caring for this patient population across care settings. IMPACT: What problem did the study address? Delirium is a common condition experienced by older hospitalized patients, but it is consistently under-recognized which has implications for patient and organization outcomes. To help address this, understanding barriers to healthcare professionals recognizing and managing delirium for this patient population is paramount. What were the main findings? Barriers to healthcare professionals recognizing and managing delirium for this patient population were synthesized in six themes: (1) healthcare professionals' knowledge and understanding, (2) communication; (3) workforce development; (4) interprofessional working; (5) confounders; and (6) organizational constraints. Where and on whom will the research have an impact? The findings of this original systematic review can contribute to hospital policy and protocol for the recognition and management of delirium in older patients. The findings can meaningfully contribute to workforce professional development for practitioners caring for older people during an acute hospital stay and for practitioners in primary and community settings involved in the follow-up of patients post hospital discharge. For researchers, the findings indicate several research recommendations including investigating the impact of an education programme for nurses and other healthcare professionals on the recognition and management of the condition and understanding and investigating how best to support delirium-related distress experienced by patients and their families and practitioners. REPORTING METHOD: This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (Page et al., 2021).

Low-dose peripheral leptin infusion produces selective activation of ventromedial hypothalamic and hindbrain STAT3.

Previous studies have shown that very low dose, acute, single peripheral leptin injections fully activate arcuate nucleus signal transducer and activator of transcription 3 (STAT3), but ventromedial hypothalamus (VMH) pSTAT3 continues to increase with higher doses of leptin that inhibit food intake. The lowest dose that inhibited intake increased circulating leptin 300-fold whereas food intake is inhibited by chronic peripheral leptin infusions that only double circulating leptin. This study examined whether the pattern of hypothalamic pSTAT3 was the same in leptin-infused rats as in leptin-injected rats. Male Sprague-Dawley rats received intraperitoneal infusions of 0, 5, 10, 20, or 40 µg leptin/day for 9 days. The highest dose of leptin increased serum leptin by 50-100%, inhibited food intake for 5 days, but inhibited weight gain and retroperitoneal fat mass for 9 days. Energy expenditure, respiratory exchange ratio, and brown fat temperature did not change. pSTAT3 was quantified in hypothalamic nuclei and the nucleus of the solitary tract (NTS) when food intake was inhibited and when it had returned to control levels. There was no effect of leptin on pSTAT3 in the medial or lateral arcuate nucleus or in the dorsomedial nucleus of the hypothalamus. VMH pSTAT3 was increased only at day 4 when food intake was inhibited, but NTS pSTAT3 was increased at both 4 and 9 days of infusion. These results suggest that activation of leptin VMH receptors contributes to the suppression of food intake, but that hindbrain receptors contribute to a sustained change in metabolism that maintains a reduced weight and fat mass.NEW & NOTEWORTHY Low-dose, chronic peripheral infusions of leptin produced an initial, transient inhibition of food intake that correlated with signal transducer and activator of transcription 3 (STAT3) activation in the ventromedial hypothalamus (VMH) and nucleus of the solitary tract (NTS). When intake normalized, but weight remained suppressed, the NTS was the only area that remained activated. These data suggest that leptin's primary function is to reduce body fat, that hypophagia is a means of achieving this and that different areas of the brain are responsible for the progressive response.

Intentional rounding: a realist evaluation using case studies in acute and care of older people hospital wards.

BACKGROUND: In response to concerns about high hospital mortality rates, patient and carer complaints, a Mid Staffordshire NHS Foundation Trust public inquiry was conducted at the request of the UK government. This inquiry found serious failures in the quality of basic care provided and as a consequence, recommended that patients should have more regular visits, organised at predictable times from nursing staff. Intentional rounding, also known as nursing ward rounds, was widely adopted to meet this need. OBJECTIVE: To test, refine or refute eight programme theories to understand what works, for whom, and in what circumstances. SETTING: Six wards (older people and acute wards) in three NHS trusts in England. PARTICIPANTS: Board level and senior nursing managers (N = 17), nursing ward staff (N = 33), allied health and medical professionals (N = 26), patients (N = 34) and relatives (N = 28) participated in an individual, in-depth interview using the realist method. In addition, ward-based nurses (N = 39) were shadowed whilst they conduced intentional rounds (240 rounds in total) and the direct care of patients (188 h of patient care in total) was observed. METHODS: The mixed methods design included: Phase (1) Theory development - A realist synthesis was undertaken to identify any programme theories which were tested, refined and/or refuted, using data from phases 2 and 3; Phase (2) A survey of all English NHS acute Trusts; Phase (3) Six case studies of wards involving realist interviews, shadowing and non-participant observations, analysis of ward outcome and cost data; and Phase (4) Synthesis of findings from phases 1, 2 and 3. RESULTS: The realist synthesis identified eight programme theories of intentional rounding: 'Consistency and comprehensiveness', 'Accountability', 'Visibility of nurses', 'Anticipation', 'Allocated time to care', 'Nurse-patient relationships', 'Multi-disciplinary teamwork and communication' and 'Patient empowerment'. Key findings showed that of the original eight programme theories of intentional rounding, only two partially explained how the intervention worked ('Consistency and comprehensiveness' and 'Accountability'). Of the remaining six programme theories, the evidence for two was inconclusive ('Visibility of nurses' and 'Anticipation') and there was no evidence for four ('Allocated time to care'; 'Nurse-patient relationships'; 'Multi-disciplinary teamwork and communication'; and 'Patient empowerment'). CONCLUSIONS: This first theory-informed evaluation of intentional rounding, demonstrates that the effectiveness of intentional rounding in the English healthcare context is very weak. Furthermore, the evidence collected in this study has challenged and refuted some of the underlying assumptions about how intentional rounding works. This study has demonstrated the crucial role context plays in determining the effectiveness of an intervention and how caution is needed when implementing interventions developed for the health system of one country into another.

'Pretty cathartic actually': Reflections on the attempt to reduce re-traumatization of researchers and nurses taking part in a longitudinal interview study.

AIM: To critically evaluate the concepts of harm and re-traumatization in the research process and to explore the ethical implications of conducting research on distressing topics using our research on the experiences of nurses working during the COVID-19 pandemic as an exemplar. DESIGN: Longitudinal qualitative interview study. METHODS: Using qualitative narrative interviews, we explored the impacts of the COVID-19 pandemic on nurses' psychological well-being in the UK. RESULTS: To reduce the potential for harm to both research participants and researchers, the members of the research team were keen to establish ways to reduce the power differential between the researcher and participants. We found that our collaborative and team-based approach, with participant autonomy and researcher reflexivity embedded into the research framework, enabled the sensitive generation of data. CONCLUSION: Reduction of potential harm for both participants and researchers in the generation of at times highly distressing data with a traumatized population was achieved through a respectful, honest and empathetic approach within a team that met frequently for reflection. IMPACT: The research participants were not harmed by our research, instead they expressed gratitude at being given space and time to tell their stories in a supportive environment. Our work advances nursing knowledge through accentuating the value of giving autonomy to research participants to control their stories whilst working within a supportive research team with emphasis placed on reflexivity and debriefing. PATIENT AND PUBLIC CONTRIBUTION: Nurses working clinically during COVID-19 were involved in the development of this study. Nurse participants were given autonomy over how and when they participated in the research process.

Speaking up during the COVID-19 pandemic: Nurses' experiences of organizational disregard and silence.

AIM: To critically examine nurses' experiences of speaking up during COVID-19 and the consequences of doing so. DESIGN: Longitudinal qualitative study. METHODS: Participants were purposively sampled to represent differing geographical locations, specialities, settings and redeployment experiences. They were interviewed (remotely) between July 2020 and April 2022 using a semi-structured interview topic guide. RESULTS: Three key themes were identified inductively from our analysis including: (1) Under threat: The ability to speak up or not; (2) Risk tolerance and avoidance: Consequences of speaking up; and (3) Deafness and hostility: Responses to speaking up. Nurses reported that their attempts to speak up typically focused on PPE, patient safety and redeployment. Findings indicate that when NHS Trusts and community services initiated their pandemic response policies, nurses' opportunities to speak up were frequently thwarted. CONCLUSION: Accounts presented in this article include nurses' feeling a sense of futility or of suffering in silence in relation to speaking up. Nurses also fear the consequences of speaking up. Those who did speak up encountered a 'deaf' or hostile response, leaving nurses feeling disregarded by their organization. This points to missed opportunities to learn from those on the front line. IMPACT: Speaking up interventions need to focus on enhancing the skills to both speak up, and respond appropriately, particularly when power, hierarchy, fear and threat might be concerned. PATIENT OR PUBLIC CONTRIBUTION: Nurses working clinically during COVID-19 were involved in the development of this study. Participants were also involved in the development of our interview topic guide and comments obtained from the initial survey helped to shape the study design.

The impact of COVID-19 on nurses (ICON) survey: Nurses' accounts of what would have helped to improve their working lives.

AIMS: To use nurses' descriptions of what would have improved their working lives during the first peak of the COVID-19 pandemic in the UK. DESIGN: Analysis of free-text responses from a cross-sectional survey of the UK nursing and midwifery workforce. METHODS: Between 2 and 14 April 2020, 3299 nurses and midwives completed an online survey, as part of the 'Impact of COVID-19 on Nurses' (ICON) study. 2205 (67%) gave answers to a question asking for the top three things that the government or their employer could do to improve their working lives. Each participants' response was coded using thematic and content analysis. Multiple response analysis quantified the frequency of different issues and themes and examined variation by employer. RESULTS: Most (77%) were employed by the National Health Service (77%) and worked at staff or senior staff nurse levels (55%). 5938 codable responses were generated. Personal protective equipment/staff safety (60.0%), support to workforce (28.6%) and better communication (21.9%) were the most cited themes. Within 'personal protective equipment', responses focussed most on available supply. Only 2.8% stated that nothing further could be done. Patterns were similar in both NHS and non-NHS settings. CONCLUSIONS: The analysis provided valuable insight into key changes required to improve the work lives of nurses during a pandemic. Urgent improvements in provision and quality of personal protective equipment were needed for the safety of both workforce and patients. IMPACT: Failure to meet nurses needs to be safe at work appears to have damaged morale in this vital workforce. We identified key strategies that, if implemented by the Government and employers, could have improved the working lives of the nursing and midwifery workforce during the early stages of the COVID-19 pandemic and could prevent the pandemic from having a longer-term negative impact on the retention of this vital workforce. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution, due to the COVID-19 Pandemic, urgency of the work and the target population being health and social care staff.

Strengthening the role of the executive nurse director: A qualitative interview study.

AIM: To explore the challenges and opportunities facing executive nurse directors in the UK and identify factors to strengthen their role and support more effective nurse leadership. DESIGN: A qualitative descriptive study using reflexive thematic analysis. METHODS: Semi-structured, telephone interviews were carried out with 15 nurse directors and 9 nominated colleagues. RESULTS: Participants described a uniquely complex role with a broader scope than any other executive board member. Seven themes were identified: preparation for the role, length of time in role, role expectations, managing complexity, status, being political and influencing. Strengthening factors included successful working relationships with other board colleagues, development of political skills and personal status, coaching and mentoring, working within a supportive team culture and having strong professional networks. CONCLUSION: Executive nurse leaders are key to the transmission of nursing values and the delivery of safety and quality in healthcare settings. To strengthen this role, the limiting factors and the recommended shared learning identified here should be recognized and addressed at an individual, organizational and professional level. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Given the pressure on all health systems to retain nurses, the role of executive nurse leaders needs to be seen as an important source of professional leadership and their value in actioning health policy into practice recognized. IMPACT: New insights have been provided into the executive nurse director role across the UK. Findings have demonstrated challenges and opportunities to strengthen the executive nurse director role. These include recognition of the need for support, preparation, networking and more realistic expectations of this unique nursing role. REPORTING METHOD: The study adhered to the Consolidated Criteria for Reporting Qualitative Research. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution.

Leptin receptor-expressing cells in the ventromedial nucleus of the hypothalamus contribute to enhanced CCK-induced satiety following central leptin injection.

Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 µg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-µg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 µg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet.NEW & NOTEWORTHY Leptin is a feedback signal in the control of energy balance, whereas cholecystokinin (CCK) is a short-term satiety signal that inhibits meal size. The two hormones synergize to promote satiety. We tested whether leptin receptors in the ventromedial nucleus of the hypothalamus (VMH) contribute to the synergy. The results suggest that there is a requirement for a baseline level of activation of leptin receptors in the VMH in order for CCK to promote satiety.

"Raising the curtain on the equality theatre": a study of recruitment to first healthcare job post-qualification in the UK National Health Service.

BACKGROUND: UK equality law and National Health Service (NHS) policy requires racial equality in job appointments and career opportunities. However, recent national workforce race equality standard (WRES) data show that nearly all NHS organisations in the UK are failing to appoint ethnically diverse candidates with equivalent training and qualifications as their white counterparts. This is problematic because workforce diversity is associated with improved patient outcomes and other benefits for staff and organisations. AIM: To better understand the reasons behind underrepresentation of ethnically diverse candidates in first NHS healthcare jobs post-qualification and to identify any structural or systemic barriers to employment for such groups. METHODS: The study was informed by critical theory and the authors' interdisciplinary perspectives as educators and researchers in the healthcare professions. Data collected from semi-structured face-to-face interviews with 12 nurse and physiotherapy recruiting managers from two NHS trusts in London were analysed using a healthcare workforce equity and diversity conceptual lens we developed from the literature. Using this lens, we devised questions to examine six dimensions of equity and diversity in the interview data from recruiting managers. RESULTS: Recruiting managers said they valued the benefits of an ethnically diverse workforce for patients and their unit/organisation. However, their adherence to organisational policies for recruitment and selection, which emphasise objectivity and standardisation, acted as constraints to recognising ethnicity as an important issue in recruitment and workforce diversity. Some recruiting managers sense that there are barriers for ethnically diverse candidates but lacked information about workforce diversity, systems for monitoring recruitment, or ways to engage with staff or candidates to talk about these issues. Without this information there was no apparent problem or reason to try alternative approaches. CONCLUSION: These accounts from 12 recruiting managers give a 'backstage' view into the reasons behind ethnic inequalities in recruitment to first healthcare job in the UK NHS. Adherence to recruitment and selection policies, which aim to support equality through standardisation and anonymisation, appear to be limiting workforce diversity and creating barriers for ethnically diverse candidates to attain the jobs that they are trained and qualified for. The Healthcare Workforce Equity + Diversity Lens we have developed can help to 'raise the curtain on the equality theatre' and inform more inclusive approaches to recruitment such as contextualised recruitment or effective allyship between employers and universities.

Nurses' and midwives' experiences and views about responding to out of work emergencies: A constructivist grounded theory study.

AIM: To explore nurses' and midwives' experiences, views, perceptions and impact on their responses to out of work emergencies where first aid may be required. DESIGN: A constructivist grounded theory study was conducted between 2012 and 2019. METHODOLOGY: In-depth, semi-structured interviews were undertaken with 16 nurses and midwives. Participants were recruited via a participant referral process with registered nurses and midwives being accessed from three NHS organizations. Data were analysed and coded using constant comparative analysis with the support of Nvivo 10 software leading to the construction of a substantive grounded theory. RESULTS: A core enduring in vivo theme, 'The Right Thing to Do', emerged as a central conceptual reality constructed via three key in vivo themes; 'Something I've Heard', 'Am I Covered?' and 'Just Who I Am', each with several sub-themes. A pervading anxiety about responding at off-duty situations requiring first aid was persistently evident across these themes. CONCLUSION: The study showed a strong sense of moral agency among nurses and midwives, despite a powerful underlying feeling of anxiety surrounding broader issues of urban myth, protection and personal and professional identity. The substantive theory emerged as 'doing "The Right Thing" in a climate of anxiety'. IMPACT: The study illuminates an area that has previously been the subject of anecdotal debate. The substantive theory, 'doing "The Right Thing" in a climate of anxiety' illustrates the issues and tensions that exist surrounding the off-duty response. Implications and recommendations for practice and education focus on the fostering of knowledge and understanding of professional identity, position in law and scope of practice, together with potential future research directions. This work provides the first in-depth qualitative study contributing a significant new perspective both nationally and globally.

'Barriers to overcoming the barriers': A scoping review exploring 30 years of clinical supervision literature.

AIMS/QUESTIONS: To explore the barriers and facilitators to nurses accessing clinical supervision; explore the barriers and facilitators to organizations implementing clinical supervision and capture what skills nurses require to facilitate clinical supervision. DESIGN: Scoping review of peer-reviewed research and grey literature. DATA SOURCES: CINAHL, Medline, PsychINFO and Scopus were searched for relevant papers published between 1990 and 2020. Google, Google Scholar, OpenGrey & EThOS were used to search for grey literature. REVIEW METHODS: PRISMA-ScR guidelines were used during the literature review process. Eighty-seven papers were included, and data were extracted from each paper using a standardized form. Data synthesis was undertaken using Seidel's analytical framework. RESULTS: Five themes were identified: Definitions and Models, (Mis) Trust and the Language of Supervision, Alternative Parallel Forums and Support Mechanisms, Time and Cost and Skills required. CONCLUSION: Since its inception in the 1990s, clinical supervision has long been regarded as a supportive platform for nurses to reflect on and develop their practice. However, this review highlights that despite an awareness of the skills required for nurses to undertake clinical supervision, and the facilitators for nurses to access and organizations to implement clinical supervision, there have been persistent barriers to implementation. This review identifies these persistent factors as 'barriers to overcoming the barriers' in the clinical supervision landscape. These require critical consideration to contribute towards moving clinical supervision forward in the spirit of its original intentions. IMPACT: This review progresses the debate on clinical supervision through critically analysing the barriers to overcoming the barriers. To this end, the review is designed to stimulate critical discussions amongst nurses in different clinical spaces and key stakeholders such as policy makers and regulatory bodies for the nursing profession.

Young Adults Rehabilitation Needs and Experiences following Stroke (YARNS): A review of digital accounts to inform the development of age-appropriate support and rehabilitation.

AIMS: To explore younger adults' experiences of stroke rehabilitation to inform practice, education and future health policy. DESIGN: Qualitative analysis of digital and other media sources on public platforms. METHODS: Between March and June 2020, the experiences of younger adult stroke survivors aged 18 to 45 at the time of the stroke were collected. Data were gathered from publicly available sources, including social media, and from English-speaking users. In total, 117 accounts from 103 participants were identified from films, autobiographical books, blogs, websites, videos, Twitter and Instagram. Data analysis followed narrative and multimodal analysis with a focus on rehabilitation needs. RESULTS: Younger adult stroke survivors make sense of their experience by reflecting on how stroke has impacted their lives. Accounts reflected an emotional journey between the past self, the present self and evolving self, as well as associated challenges such as the impact on relationships and careers. The majority of accounts presented transitions as problematic, including the receipt of the initial diagnosis, or sometimes misdiagnosis, to returning home and achieving long-term rehabilitation goals. Specialist stroke nurses were considered essential in the rehabilitation process. CONCLUSION: A complex process of recovery follows stroke for younger adult stroke populations. Challenges to the rehabilitation process need to be better understood and the role of nursing highlighted in future service provision. A series of age-related challenges were highlighted that require attention to improve the care and support offered. IMPACT: This article informs clinicians, educators, and policymakers of the age-related needs of young adult stroke survivors. Focusing on the individual and the development of age-appropriate person-centred stroke care is important. The study highlights the role of stroke nursing and challenges the current policy focus on older stroke populations as well as arguing for greater awareness of age-appropriate stroke rehabilitation in younger adults following stroke.

Phosphorylation of STAT3 in hypothalamic nuclei is stimulated by lower doses of leptin than are needed to inhibit food intake.

This experiment investigated which hypothalamic nuclei were activated by a dose of leptin that inhibited food intake. Foodnot intake, energy expenditure, respiratory exchange ratio (RER), and intrascapular brown adipose tissue (IBAT) temperature were measured in male and female Sprague Dawley rats for 36 h following an intraperitoneal injection of 0, 50, 200, 500, or 1,000 µg leptin/kg with each rat tested with each dose of leptin in random order. In both males and females, RER and 12-h food intake were inhibited only by 1,000 µg leptin/kg, but there was no effect on energy expenditure or IBAT temperature. At the end of the experiment, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) immunoreactivity was measured 1 h after injection of 0, 50, 500, or 1,000 µg leptin/kg. In male rats, the lowest dose of leptin produced a maximal activation of STAT3 in the Arc and nucleus of the solitary tract (NTS). There was no response in the dorsomedial hypothalamus, but there was a progressive increase in ventromedial nucleus of the hypothalamus (VMH) pSTAT3 with increasing doses of leptin. In female rats, there was no significant change in Arc and pSTAT3 NTS activation was maximal with 500 mg leptin/kg, but only the highest dose of leptin increased VMH pSTAT3. These results suggest that the VMH plays an important role in the energetic response to elevations of circulating leptin but do not exclude the possibility that multiple nuclei provide the appropriate integrated response to hyperleptinemia.NEW & NOTEWORTHY The results of this experiment show that doses of leptin too small to inhibit food intake produce a maximal response to leptin in the arcuate nucleus. By contrast the VMH shows a robust response that correlates with inhibition of food intake. This suggests that the VMH plays an important role in the energetic response to hyperleptinemia.

Consuming sucrose solution promotes leptin resistance and site specifically modifies hypothalamic leptin signaling in rats.

Rats consuming 30% sucrose solution and a sucrose-free diet (LiqS) become leptin resistant, whereas rats consuming sucrose from a formulated diet (HS) remain leptin responsive. This study tested whether leptin resistance in LiqS rats extended beyond a failure to inhibit food intake and examined leptin responsiveness in the hypothalamus and hindbrain of rats offered HS, LiqS, or a sucrose-free diet (NS). Female LiqS Sprague-Dawley rats initially only partially compensated for the calories consumed as sucrose, but energy intake matched that of HS and NS rats when they were transferred to calorimetry cages. There was no effect of diet on energy expenditure, intrascapular brown fat tissue (IBAT) temperature, or fat pad weight. A peripheral injection of 2 mg of leptin/kg on day 23 or day 26 inhibited energy intake of HS and NS but not LiqS rats. Inhibition occurred earlier in HS rats than in NS rats and was associated with a smaller meal size. Leptin had no effect on energy expenditure but caused a transient rise in IBAT temperature of HS rats. Leptin increased the phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in the hindbrain and ventromedial hypothalamus of all rats. There was a minimal effect of leptin in the arcuate nucleus, and only the dorsomedial hypothalamus showed a correlation between pSTAT3 and leptin responsiveness. These data suggest that the primary response to leptin is inhibition of food intake and the pattern of sucrose consumption, rather than calories consumed as sucrose, causes leptin resistance associated with site-specific differences in hypothalamic leptin signaling.

Loss of leptin receptor-expressing cells in the hindbrain decreases forebrain leptin sensitivity.

Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin. Injections of leptin-conjugated saporin (Lep-Sap) into the medial nucleus of the solitary tract (NTS) were used to destroy hindbrain leptin receptor-expressing neurons of male Sprague-Dawley rats. Controls were injected with saporin conjugated with a nonsense peptide (Blk-Sap). Lep-Sap had no effect on daily food intake or body weight, but expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the NTS following a peripheral injection of leptin was abolished 26 days after Lep-Sap injections. To test forebrain leptin sensitivity, Lep-Sap and Blk-Sap rats received third-ventricle injections of 0, 0.05, 0.1, 0.25, or 0.5 µg leptin. Food intake was inhibited by 0.25 and 0.5 µg leptin in Blk-Sap rats, but there was no significant effect of leptin on food intake of Lep-Sap rats. There was no difference in hypothalamic pSTAT3 in unstimulated conditions, but pSTAT3 was lower in the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH) of Lep-Sap rats compared with Blk-Sap rats following a third-ventricle injection of 0.25 µg leptin. These results are consistent with previous data showing that loss of VMH leptin receptor-expressing cells prevents weight loss caused by fourth-ventricle leptin infusion and show that the integrated response between the hindbrain and forebrain is heavily dependent on leptin activity in the VMH.

Chronic exposure to liquid sucrose and dry sucrose diet have differential effects on peripheral taste responses in female rats.

Sugar-sweetened beverages are the major source of added calories in the Western diet and their prevalence is associated with obesity and metabolic disruption. Despite the critical role of the taste system in determining food selection and consumption, the effects of chronic sucrose consumption on the peripheral taste system in mammals have received limited attention. We offered female Sprague Dawley rats free access to water and one of three diets for up to 40 days: (1) sucrose-free chow or "NS" diet; (2) a high-sucrose dry diet or "HS"; or (3) 30% sucrose solution and the NS diet, designated "LiqS" diet. Sucrose consumption by LiqS rats gradually increased and by day 14 was equal to that of HS rats. Food intake decreased in LiqS rats, but their energy intake remained higher than for NS or HS rats. There was no significant difference in weight gain of the groups during the study. Recordings from the chorda tympani nerve (CT), which innervates taste buds on the anterior tongue, revealed decreased responses to 1 M sucrose in both LiqS and HS rats and to acesulfame K and salt tastants in LiqS rats after 40 days on diet. Umami, bitter, and acid response magnitudes were unchanged in both groups. These results demonstrate that chronic sucrose exposure inhibits taste responses to higher concentrations of sweet stimuli. More surprisingly, CT responses to NaCl and 0.5M NaAc were significantly reduced in rats on the LiqS diet. Thus, the physical form of the diet influences taste responsiveness to salt and sweet taste function. These data suggest that taste buds are previously unappreciated targets of chronic sucrose consumption.

Low-dose infusions of leptin into the nucleus of the solitary tract increase sensitivity to third ventricle leptin.

Previous studies suggest that weight loss occurs when leptin receptors in both the forebrain and hindbrain are activated. Experiments described here tested whether this integration is mediated through a neural connection or by leptin diffusion through the subarachanoid space. If the hypothalamus and hindbrain communicated through a neural pathway, then a very low dose of leptin infused directly into the nucleus of the solitary tract (NTS) would enhance the response to third ventricle (3V) leptin but would have no effect if infused into the fourth ventricle (4V). A 12-day infusion of 10 ng/24 h into the 4V or the NTS reduced body fat. Leptin at 5 ng/24 h into the 4V or NTS had no effect on food intake or body composition, but infusion of 5 ng of leptin/24 h into the NTS combined with a 3V injection of 0.1 µg of leptin inhibited food intake between 6 and 12 h after injection. Cumulative intake was inhibited for up to 36 h. 3V leptin had no effect on food intake of rats receiving the 4V leptin infusion. Similar results were found using infusions of 5 ng leptin/24 h and a 3V injection of 0.025 µg leptin. These data suggest that activation of leptin receptors in the NTS lowers the threshold for response to leptin in the forebrain through a neural network.

Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions.

Leptin administration into the hindbrain, and specifically the nucleus of the solitary tract, increases phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation, in hypothalamic nuclei known to express leptin receptors. The ventromedial nucleus of the hypothalamus (VMH) shows the greatest response, with a threefold increase in pSTAT3. This experiment tested the importance of VMH leptin receptor-expressing neurons in mediating weight loss caused by fourth ventricle (4V) leptin infusion. Male Sprague-Dawley rats received bilateral VMH 75-nL injections of 260 ng/µL of leptin-conjugated saporin (Lep-Sap) or blank-saporin (Blk-Sap). After 23 days they were fitted with 4V infusion cannulas and 1 wk later adapted to housing in a calorimeter before they were infused with 0.9 µg leptin/day for 14 days. There was no effect of VMH Lep-Sap on weight gain or glucose clearance before leptin infusion. Leptin inhibited food intake and respiratory exchange ratio in Blk-Sap but not Lep-Sap rats. Leptin had no effect on energy expenditure or brown adipose tissue temperature of either group. Inguinal and epididymal fat were significantly reduced in leptin-treated Blk-Sap rats, but the response was greatly attenuated in Lep-Sap rats. VMH pSTAT3 was increased in leptin-treated Blk-Sap but not Lep-Sap rats. These results support the concept that leptin-induced weight loss results from an integrated response across different brain areas. They also support previous reports that VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions but limit weight gain during positive energy balance.

Development of leptin resistance in sucrose drinking rats is associated with consuming carbohydrate-containing solutions and not calorie-free sweet solution.

Rats offered 30% sucrose solution plus chow or a sucrose-free diet develop leptin resistance within 4 weeks. This experiment tested whether leptin resistance was associated with the reward of sweet taste or the pre- or post-absorptive effects of consumption of simple carbohydrate. Male Sprague Dawley rats were offered a sucrose-free diet (NS), a diet containing 67% calories as sucrose (HS) or NS diet plus 30% sucrose (LS), 0.03% saccharin (Sacc) or 20% SolCarb® solution for 38 days. SolCarb® is a maltodextrin powder. Sacc rats initially drank more than LS rats, but intakes were the same after Day 20. SolCarb® and LS rats drank the same number of calories from Day 15 to the end of the experiment. SolCarb® and LS rats ate less dry food than other groups, but total energy intake was greater than that of NS, HS and Sacc groups and over 80% of their energy intake was from carbohydrate. Leptin responsiveness was tested on Days 27 and 32 with each rat acting as its own control. An i.p. injection of 2 mg/kg leptin inhibited food intake of NS, HS and Sacc rats, but had no effect on energy intake of LS or SolCarb® rats or on consumption of Sacc, sucrose or SolCarb® solution. At the end of the experiment all of the rats were insulin sensitive, had the same body composition and serum leptin concentrations. These data indicate that consumption of a calorie containing carbohydrate solution and not sweet taste drives the development of leptin resistance and suggest that there is lower threshold for inhibition of hunger than for inhibition of reward by leptin.

Source of dietary sucrose influences development of leptin resistance in male and female rats.

Male rats offered 30% sucrose solution in addition to chow develop leptin resistance without an increase in energy intake or body fat. This study tested whether the leptin resistance was dependent on the physical form of the sucrose. Sprague-Dawley rats were offered a sucrose-free (NS) diet, a 66.6% of energy as sucrose (HS) diet, or the NS diet + 30% sucrose solution (LS). Sucrose intake of LS rats equaled that of HS rats, but total carbohydrate intake exceeded that of HS rats. After 33 days, male and female LS rats were resistant to the inhibitory effect of peripherally administered leptin on food intake. LS rats drank small, frequent meals of sucrose during light and dark periods, whereas HS rats consumed more meals during the dark than the light period and remained responsive to leptin. Diet did not affect daily energy intake or insulin sensitivity. There was a small increase in body fat in the female rats. Leptin sensitivity was restored within 5 days of withdrawal from sucrose in male LS rats. This rapid reversal suggested that leptin resistance was associated with the metabolic impact of drinking sucrose. An experiment was carried out to test whether activity of the hexosamine biosynthetic pathway and glycation of leptin signaling proteins were increased in LS rats, but the results were equivocal. A final experiment determined that female LS rats were leptin-resistant within 18 days of access to sucrose solution and that the small, but significant, increase in body fat was associated with increased adipocyte glucose utilization and insulin responsiveness, which may have been secondary to adipocyte leptin resistance.