5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation.

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

Primary care barriers and facilitators to nonpharmacologic treatments for low back pain: A qualitative pilot study.

BACKGROUND: Clinical practice guidelines encourage primary care providers (PCPs) to recommend nonpharmacologic treatment as first-line therapy for low back pain (LBP). However, the determinants of nonpharmacologic treatment use for LBP in primary care remain unclear, particularly in low-income settings. OBJECTIVE: To pilot a framework-informed interview guide and codebook to explore determinants of nonpharmacologic treatment use in primary care. METHODS: In this qualitative interview study, we enrolled PCPs and community health workers (CHWs) from four primary care clinics at a safety net hospital. A semistructured interview guide informed by the Consolidated Framework for Implementation Research (CFIR) guided inquiry on barriers/facilitators to nonpharmacologic treatments for LBP (eg, acupuncture, chiropractic care, physical therapy). We included questions on whether current CHW roles may address barriers to nonpharmacologic treatment use. Interviews were audio-recorded, transcribed verbatim, and independently coded by four investigators. An a priori codebook composed of CFIR determinants and known CHW roles guided deductive content analysis to identify major themes. RESULTS: Eight individuals (six PCPs, two CHWs; age range: 32-51 years, five female) participated in hour-long interviews. Half had worked at the hospital for ≥15 years and all reported seeing patients with LBP (range: 2-20 patients per week). All participants identified the following CFIR factors as barriers/facilitators: nonpharmacologic treatment characteristics (perceived cost, relative advantage compared to other treatments); outer setting (patient needs/resources, limited connections with community-based nonpharmacologic treatment) and PCP characteristics (attitudes/beliefs about nonpharmacologic treatments). Although participants indicated several CHW roles could be adapted to address barriers (eg, care coordination, resource linking, case management), other roles seemed less feasible (eg, targeted health education) in our health care system. CONCLUSIONS: Preliminary insight on key determinants of nonpharmacologic treatments for LBP should be further examined in large multisite studies. Future studies may also determine whether a CHW-led strategy can improve nonpharmacologic treatment access and clinical outcomes in primary care.

Research Protocol Adaptations During the COVID-19 Pandemic: A Process Evaluation.

In general, COVID-19-related adaptations that transitioned in-person assessments and interventions to a virtual format were not routinely evaluated. We aimed to conduct a process evaluation to examine the impact of COVID-19-related adaptations on a behavior change intervention designed to increase exercise adherence among Veterans with mobility difficulty. We used secondary data from a nonrandomized study to complete a process evaluation examining the intervention's reach, recruitment, fidelity, dose delivered by physical therapists, and the dose received by the 14 participating Veterans. The physical therapist delivered 95% (133/140) of the study's 10 sessions. Sessions with the lowest delivery dose included Sessions 1 and 10 (86%; n = 12/14). The elements with the lowest dose received included using an exercise journal and developing a postintervention plan (86%; n = 12/14). Our COVID-19 adaptations allowed us to provide our intervention to the majority (67%) of eligible participants without a negative impact on fidelity, dose delivered, or dose received.

Trends in Chiropractic Care and Physical Rehabilitation Use Among Adults with Low Back Pain in the United States, 2002 to 2018.

BACKGROUND: While nonpharmacologic treatments are increasingly endorsed as first-line therapy for low back pain (LBP) in clinical practice guidelines, it is unclear if use of these treatments is increasing or equitable. OBJECTIVE: Examine national trends in chiropractic care and physical rehabilitation (occupational/physical therapy (OT/PT)) use among adults with LBP. DESIGN/SETTING: Serial cross-sectional analysis of the National Health Interview Survey, 2002 to 2018. PARTICIPANTS: 146,087 adults reporting LBP in prior 3 months. METHODS: We evaluated the association of survey year with chiropractic care or OT/PT use in prior 12 months. Logistic regression with multilevel linear splines was used to determine if chiropractic care or OT/PT use increased after the introduction of clinical guidelines. We also examined trends in use by age, sex, race, and ethnicity. When trends were similar over time, we present differences by these demographic characteristics as unadjusted ORs using data from all respondents. RESULTS: Between 2002 and 2018, less than one-third of adults with LBP reported use of either chiropractic care or OT/PT. Rates did not change until 2016 when uptake increased with the introduction of clinical guidelines (2016-2018 vs 2002-2015, OR = 1.15; 95% CI: 1.10-1.19). Trends did not differ significantly by sex, race, or ethnicity (p for interactions > 0.05). Racial and ethnic disparities in chiropractic care or OT/PT use were identified and persisted over time. For example, compared to non-Hispanic adults, either chiropractic care or OT/PT use was lower among Hispanic adults (combined OR = 0.62, 95% CI: 0.65-0.73). By contrast, compared to White adults, Black adults had similar OT/PT use (OR = 0.98; 95% CI: 0.94-1.03) but lower for chiropractic care use (OR = 0.50; 95% CI: 0.47-0.53). CONCLUSIONS: Although use of chiropractic care or OT/PT for LBP increased after the introduction of clinical guidelines in 2016, only about a third of US adults with LBP reported using these services between 2016 and 2018 and disparities in use have not improved.

Defining Clinically Meaningful Cut Points for Leg Power Impairment Using Physical Performance in Older Adults: A Secondary Analysis From Boston RISE.

OBJECTIVE: To identify clinically meaningful thresholds of leg power impairment identified by the stair climb power test (SCPT). DESIGN: Cross-sectional analysis using the baseline data from an observational cohort study. SETTING: The Boston Rehabilitative Impairment Study of the Elderly. PARTICIPANTS: Community-dwelling older adults (N=413). MAIN OUTCOME MEASURES: SCPT and the Short Physical Performance Battery (SPPB). RESULTS: Using the receiver operating characteristic curves and Youden's J statistics, the optimal threshold for the SCPT associated with mobility limitation as defined by an SPPB score ≤9 was 3.07 Watts/kg for men with a sensitivity of 74%, a specificity of 73% and, an area under the curve (AUC) value of 0.78. For women, the optimal threshold was 2.59 Watts/kg with a sensitivity of 83%, a specificity of 69%, and an AUC value of 0.81. The classification and regression tree sensitivity analysis demonstrated similar thresholds, 2.88 Watts/kg and 2.53 Watts/kg for men and women, respectively. CONCLUSIONS: The study identified clinically meaningful thresholds of impairment for the SCPT for mobility limited older primary care patients. These thresholds may be used to inform rehabilitation care to improve functional mobility of older adults and should be validated in larger more representative clinical trials.

Defining and Measuring Preclinical Mobility Limitation: An Expert Consensus Exercise Informed by a Scoping Review.

BACKGROUND: Early change in function in older adults has been termed preclinical disability (PCD). PCD has been understudied compared to other stages of disability because it is unlikely to receive comparative priority in clinical settings. It has major implications for prevention and population health as it may be the optimal time to intervene to prevent further decline. A standardized approach to research in PCD, including a common definition and measurement approaches, is needed to advance this work. METHODS: The process to establish how PCD should be defined and measured was undertaken in 2 stages: (1) a scoping review of the literature, which was used to inform (2) a web-enabled consensus meeting with content experts. RESULTS: The scoping review and the consensus meeting support the use of the term preclinical mobility limitation (PCML) and that it should be measured using both patient-reported and performance-based measures. It was agreed that the definition of PCML should include modification of frequency and/or method of task completion, without overt disability, and that requisite mobility tasks include walking (distance and speed), stairs, and transfers. CONCLUSIONS: Currently, there are few standardized assessments that can identify PCML. PCML is the term that most clearly describes the stage where people experience a change in routine mobility tasks, without a perception of disability. Further evaluation into the reliability, validity, and responsiveness of outcome measures is needed to advance research on PCML.

Developing and Testing Implementation Strategies to support the Centers for Disease Control and Prevention's Initiative for Falls Risk Management in Outpatient Physical Therapy: A Protocol.

Objectives: To develop and test implementation strategies to support implementing the Centers for Disease Control and Preventions' Stopping Elderly Accidents, Deaths, and Injuries (STEADI) initiative for falls prevention and falls risk management in a novel setting, outpatient physical therapy. Design: A feasibility implementation study engaging key partners involved in or affected by the implementation throughout the study. Setting: Five outpatient physical therapy clinics embedded in a health system. Participants: Key partners (physical therapists, physical therapist assistants, referring physicians, administrative clinic staff, older adults, and caregivers) involved in or affected by the implementation (N=48) will participate in surveys and interviews to identify barriers and facilitators prior to implementation and post implementation. Twelve key partners representing at least 1 of each group will participate in evidence-based quality improvement panels to identify which barriers and facilitators are most important and feasible to address and to assist in choosing and designing implementation strategies to support the uptake of STEADI in outpatient rehabilitation. STEADI will be implemented in 5 outpatient physical therapy clinics as a standard of care for the ∼1200 older adults attending those clinics annually. Outcomes: Primary outcomes include clinic- and provider-level (physical therapists and physical therapist assistant) adoption and fidelity to STEADI screening, multifactorial assessment, and falls risk interventions for older adults (65 years or older) attending outpatient physical therapy. Key partners' perceived feasibility, acceptability, and appropriateness of STEADI in outpatient physical therapy will also be measured using validated implementation science questionnaires. Exploratory clinical outcomes of older adults' falls risk pre- and post rehabilitation will be investigated.

Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Frailty and Time at Home After Post-Acute Care in Skilled Nursing Facilities.

OBJECTIVES: To examine the association of a claims-based frailty index with time at home, defined as the number of days alive and spent out of hospital or skilled nursing facility (SNF). DESIGN: Cohort Study. SETTING AND PARTICIPANTS: A 5% Medicare random sample of fee-for-service beneficiaries, who had continuous part A and B enrollment in the prior 6 months, that were discharged from a short SNF admission in 2014‒2016. METHODS: Frailty was measured with a validated claims-based frailty index (CFI) (range: 0‒1, higher scores indicating worse frailty) and categorized into nonfrail (CFI <0.25), mild frailty (CFI 0.25‒0.34), and moderate-to-severe frailty (CFI ≥0.35). We measured home time in the 6 months following SNF discharge (range: 0‒182 days with higher values representing more days at home and thus a better outcome). We used logistic regression to assess the association between frailty and short home time, defined as <173 days, adjusting for age, sex, race, region, a comorbidity index, clinical SNF admission characteristics in the Minimum Data Set, and SNF characteristics. RESULTS: In our sample of 144,708 beneficiaries (mean age, 80.8 years, 64.9% female, 85.9% white) who were discharged to community after SNF stay, the mean CFI was 0.26 (standard deviation, 0.07). The mean home time was 165.6 (38.1) days in nonfrail, 154.4 (47.4) days in mild frailty, 145.0 (52.0) days in moderate-to-severe frailty group. After full model adjustments, moderate to severe frailty was associated with a 1.71 (95% CI 1.65‒1.78) higher odds of having short time at home in the 6 months following SNF discharge. CONCLUSION AND IMPLICATIONS: Higher CFI is associated with short time at home in Medicare beneficiaries who are discharged to the community after post-acute SNF stay. Our results support the utility of CFI in identifying SNF patients who need additional resources and interventions to prevent health decline and poor quality of life.

Prevalence and Predictors of Ambulatory Care Physicians' Documentation of Mobility Limitations in Older Adults.

OBJECTIVE: To determine how often physicians document mobility limitations in visits with older adults, and which patient, physician, and practice characteristics associate with documented mobility limitations. DESIGN: We completed a cross-sectional analysis of National Ambulatory Medical Care Surveys, years 2012-2016. Multivariate analyses were conducted to identify patient, physician, and practice-level factors associated with mobility limitation documentation. SETTING: Ambulatory care visits. PARTICIPANTS: We analyzed visits with adults 65 years and older. Final sample size represented 1.3 billion weighted visits. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: We defined the presence/absence of a mobility limitation by whether any International Classification of Diseases (ICD)-9 or ICD-10 code related to mobility limitations, injury codes, or the patient's "reasons for visit" were documented in the visits. RESULTS: The overall prevalence of mobility limitation documentation was 2.4%. The most common codes were falls-related. Patient-level factors more likely to be associated with mobility limitation documentation were visits by individuals over 85 years of age, relative to 65-69 years, (odds ratio 2.32, 95% confidence interval 1.76-3.07]; with a comorbid diagnosis of arthritis (odds ratio 1.35, 1.18-2.01); and with a comorbid diagnosis of cerebrovascular disease (odds ratio 1.60, 1.13-2.26). Patient-level factors less likely to be associated with mobility limitation documentation were visits by men (odds ratio 0.80, 0.64-0.99); individuals with a cancer diagnosis (odds ratio 0.76, 0.58-0.99); and by individuals seeking care for a chronic problem (relative to a new problem [odds ratio 0.36, 0.29-0.44]). Physician-level factors associated with an increased likelihood of mobility limitation documentation were visits to neurologists (odds ratios 4.48, 2.41-8.32) and orthopedists (odds ratio 2.67, 1.49-4.79) compared with primary care physicians. At the practice-level, mobility documentation varied based on the percentage of practice revenue from Medicare. CONCLUSIONS: Mobility limitations are under-documented and may be primarily captured when changes in function are overt.

Changes in Mild Neurocognitive Disorder Status in Mobility Limited Older Primary Care Patients: Implications for Rehabilitative Care.

OBJECTIVE: The aim of the study is to identify potential rehabilitative treatment targets associated with participants' annual cognitive status. DESIGN: A cohort study patients with self-reported mobility limitation who completed neuropsychological, physical performance testing, and questionnaires at baseline to 2-year follow-up were categorized into three groups (persistently cognitively normal, nonpersistent mild neurocognitive disorder, and persistently mild neurocognitive disorder) based on their annual cognitive status using baseline, years 1 and 2 performance on Hopkins Verbal Learning, Trail Making, and Digit Symbol Substitution Tests. Repeated measures multinomial regression analysis was used to examine the differences between groups and associated characteristics. RESULTS: Study included 349 participants (mean age, 76 ± 7) with 57% of participants were persistently cognitively normal, 16% persistently mild neurocognitive disorder, and 27% nonpersistent mild neurocognitive disorder over 2 yrs of follow-up. Faster gait speed (relative risk reduction, 0.64-0.89) was associated with risk reduction and increase in depressive symptoms (relative risk reduction, 1.09-1.12) was associated with greater risk of being classified into the nonpersistent or persistently mild neurocognitive disorder compared with persistently cognitively normal. CONCLUSIONS: Variability across cognitive status over time was observed. Gait speed and depressive symptoms were modifiable risk factors associated with nonpersistent and persistent mild neurocognitive disorder status. This study reinforces the potential benefit of multifaceted rehabilitation for preventing and treating older adults with mobility and/or cognitive problems.

An innovative rehabilitation program for the veterans affairs post-acute skilled nursing setting: Preliminary results.

BACKGROUND: Skilled nursing rehabilitative care plays a critical role in older adults' functional recovery impacting post-discharge outcomes. Variations across post-acute rehabilitative care services and patient outcomes indicate a need to improve rehabilitative care in this setting. We adapted a successful outpatient care program (Live Long Walk Strong-LLWS) to address this need in post-acute care settings within the Veterans Health Administration. LLWS differs from standard PT care by treating impairments linked to functional decline that are not traditionally targeted by standard care, providing formalized coaching to optimize behavior change, and providing post-discharge case management to optimize long-term outcomes. The purpose was to adapt, refine and implement the LLWS program for the Community Living Center (CLC), determine its acceptability and feasibility, and evaluate its preliminary effectiveness among older adults. METHODS: The design of the program was adapted from the original outpatient LLWS program to the CLC setting through quality improvement methods and the Replicating Effective Programs (REP) framework. Primary outcomes included measures of feasibility and acceptability of >80% enrollment and completion of sessions as well as preliminary effectiveness using performance-based and patient-reported measures of function including the Short Physical Performance Battery (SPPB), AM-PAC, a Global Rating of Change questionnaire, and a satisfaction survey. RESULTS: After 18 months, 51 Veterans had enrolled in the LLWS program, with 94.1% maintaining enrollment. We observed >80% completion of the inpatient and home follow-up sessions. Most patients were highly satisfied with care. Improvements in the SPPB (2.3 (SD 2.2) points), gait speed (0.17 (0.14) m/s) and the AM-PAC (6.5 (SD 5.7)) surpassed clinically meaningful thresholds. CONCLUSIONS: This novel care program is feasible and acceptable to Veterans, demonstrating preliminary effectiveness with improving functional outcomes. Future research is needed to further examine the program's impact on other important outcomes relative to standard modes of care.

Hypothalamic Grb10 enhances leptin signalling and promotes weight loss.

Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.

Age-related changes in gait biomechanics and their impact on the metabolic cost of walking: Report from a National Institute on Aging workshop.

Changes in old age that contribute to the complex issue of an increased metabolic cost of walking (mass-specific energy cost per unit distance traveled) in older adults appear to center at least in part on changes in gait biomechanics. However, age-related changes in energy metabolism, neuromuscular function and connective tissue properties also likely contribute to this problem, of which the consequences are poor mobility and increased risk of inactivity-related disease and disability. The U.S. National Institute on Aging convened a workshop in September 2021 with an interdisciplinary group of scientists to address the gaps in research related to the mechanisms and consequences of changes in mobility in old age. The goal of the workshop was to identify promising ways to move the field forward toward improving gait performance, decreasing energy cost, and enhancing mobility for older adults. This report summarizes the workshop and brings multidisciplinary insight into the known and potential causes and consequences of age-related changes in gait biomechanics. We highlight how gait mechanics and energy cost change with aging, the potential neuromuscular mechanisms and role of connective tissue in these changes, and cutting-edge interventions and technologies that may be used to measure and improve gait and mobility in older adults. Key gaps in the literature that warrant targeted research in the future are identified and discussed.

Mild Neurocognitive Disorder, Social Engagement, and Falls Among Older Primary Care Patients.

OBJECTIVES: (1) To estimate the association between social engagement (SE) and falls; (2) To examine the relation between mild neurocognitive disorder (MNCD) and falls by different levels of SE. DESIGN: We performed a secondary data analysis using prospective cohort study design. SETTING: Primary care. PARTICIPANTS: A total of 425 older adult primary care patients at risk for mobility decline (N=425). As previously reported, at baseline, 42% of participants exhibit MNCD. MAIN OUTCOME MEASURES: The outcome variable was the number of falls during 2 years of follow-up. Exposure variables at baseline included (1) MNCD identified using a cut-off of 1.5 SD below the age-adjusted mean on at least 2 measures within a cognitive performance battery and (2) SE, which was assessed using the social component of the Late-Life Function and Disability Instrument. High SE was defined as having a score ≥ median value (≥49 out of 100). All models were adjusted for age, sex, education, marital status, comorbidities, and pain status. RESULTS: Over 2 years of follow-up, 48% of participants fell at least once. MNCD was associated with a higher rate of falls, adjusting for the covariates (Incidence Rate Ratio=1.6, 95% confidence interval: 1.1-2.3). There was no significant association between MNCD and the rate of falls among people with high SE. In participants with low SE (having a score less than 49.5 out 100), MNCD was associated with a higher rate of falls as compared with participants with no neurocognitive disorder (No-NCD). CONCLUSIONS: Among participants with low SE, MNCD was associated with a higher rate of falls, but not among participants with high SE. The findings suggest that high SE may be protective against falls among older primary care patients with MNCD.

Incorporating Physical Activity Assessments and Behavior Change Techniques Into Geriatrics.

Ninety-one percent of adults 65 years and older do not perform the recommended levels of physical activity (PA), resulting in increased risk of disability, morbidity, and mortality. Despite knowing the benefits of PA and acknowledging the importance of assessing and addressing inadequate PA levels, 50%-75% of health care providers do not incorporate behavior change techniques into clinical practice. This clinical gap can be explained by a lack of knowledge or confidence in (1) assessing PA levels; (2) addressing inadequate PA levels; and (3) justifying the time needed to use these techniques in clinical practice. In this special communication, we address this gap by providing a 3-step theoretical-based clinical decision pathway that guides health care providers on how to identify older adults with inadequate PA levels, determine readiness to increase PA, and empower patents to develop an action plan that will increase their PA levels. We also provide a conceptual model that supports the use of techniques that assess and address inadequate PA by tying PA to the Age-Friendly Health System's 4Ms (ie, What Matters to the older adult, Mentation, Mobility, and Medications).

Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior.

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT2CR is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.

SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis.

BACKGROUND: Pro-opiomelanocortin (POMC) neurons play a sexually dimorphic role in body weight and glucose balance. However, the mechanisms for the sex differences in POMC neuron functions are not fully understood. RESULTS: We detected small conductance calcium-activated potassium (SK) current in POMC neurons. Secondary analysis of published single-cell RNA-Seq data showed that POMC neurons abundantly express SK3, one SK channel subunit. To test whether SK3 in POMC neurons regulates POMC neuron functions on energy and glucose homeostasis, we used a Cre-loxP strategy to delete SK3 specifically from mature POMC neurons. POMC-specific deletion of SK3 did not affect body weight in either male or female mice. Interestingly, male mutant mice showed not only decreased food intake but also decreased physical activity, resulting in unchanged body weight. Further, POMC-specific SK3 deficiency impaired glucose balance specifically in female mice but not in male mice. Finally, no sex differences were detected in the expression of SK3 and SK current in total POMC neurons. However, we found higher SK current but lower SK3 positive neuron population in male POMC neurons co-expressing estrogen receptor α (ERα) compared to that in females. CONCLUSION: These results revealed a sexually dimorphic role of SK3 in POMC neurons in both energy and glucose homeostasis independent of body weight control, which was associated with the sex difference of SK current in a subpopulation of POMC + ERα + neurons.