Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood.

RATIONALE: Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective because of UCP1 (uncoupling protein 1)-dependent thermogenesis. OBJECTIVE: We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression. METHODS AND RESULTS: Using mouse models of atherosclerosis housed at 3 different ambient temperatures, we observed that cold temperature enhanced, whereas thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1. However, whereas UCP1 deficiency promoted poor glucose tolerance, thermoneutral housing enhanced glucose tolerance, and this effect held even in the context of UCP1 deficiency. In conditions of thermoneutrality, but not UCP1 deficiency, circulating monocyte counts were reduced, likely accounting for fewer monocytes entering plaques. Reductions in circulating blood monocytes were also found in a large human cohort in correlation with environmental temperature. By contrast, reduced plaque growth in mice lacking UCP1 was linked to lower cholesterol. Through application of a positron emission tomographic tracer to track CCR2+ cell localization and intravital 2-photon imaging of bone marrow, we associated thermoneutrality with an increased monocyte retention in bone marrow. Pharmacological activation of ß3-adrenergic receptors applied to mice housed at thermoneutrality induced UCP1 in beige fat pads but failed to promote monocyte egress from the marrow. CONCLUSIONS: Warm ambient temperature is, like UCP1 deficiency, atheroprotective, but the mechanisms of action differ. Thermoneutrality associates with reduced monocyte egress from the bone marrow in a UCP1-dependent manner in mice and likewise may also suppress blood monocyte counts in man.

Methadone vs. Buprenorphine for In-Hospital Initiation: Which Is Better for Outpatient Care Retention in Patients with Opioid Use Disorder?

INTRODUCTION: Currently, few hospitals provide medications for opioid use disorder (MOUD) to admitted patients with opioid use disorder (OUD). Data are needed to inform whether the choice of medication during hospitalization influences probability of retention in outpatient OUD treatment. METHODS: This was a retrospective cohort analysis of patients who received a medical toxicology consult for OUD. Medical records were reviewed to determine if patients received MOUD and were referred to Engaging Patients in Care Coordination (EPICC), a service that connects hospitalized patients with OUD to outpatient care. Patients were stratified by the last form of MOUD they received in the hospital (methadone verses buprenorphine); retention in outpatient treatment was measured at 2 weeks, 30 days, and 12 weeks. The log-rank test was used to determine the difference in probabilities of retention in the methadone and buprenorphine groups. An event was defined as drop-out from outpatient treatment. RESULTS: Of 267 total patients with medical toxicology consults for OUD, 155 received MOUD and referral to EPICC. One hundred six patients received buprenorphine and 46 received methadone. Three additional patients were excluded. The rate of retention in outpatient treatment for patients who received buprenorphine was 37%, 26%, and 13% and for patients who received methadone was 43%, 39%, and 35% at 2 weeks, 30 days, and 12 weeks, respectively. Methadone was associated with a statistically significant increased probability of retention in outpatient treatment as compared to buprenorphine (P < 0.01). CONCLUSION: Despite the limitations of this retrospective study, in hospitalized patients who received MOUD, the probability of retention in outpatient treatment was higher in patients receiving methadone compared to buprenorphine.

B Cell-Mediated Antigen Presentation through MHC Class II Is Dispensable for Atherosclerosis Progression.

Depletion of B cells attenuates plaque development and modulates T cell responses in mouse models of atherosclerosis, suggesting that Ag presentation by B cells may promote disease progression. Thus, we set out to determine the role of B cell-mediated MHC class II (MHC II) Ag presentation during atherosclerotic plaque development. We developed murine conditional MHC II deletion and expression systems under control of the B cell-restricted CD19 promoter in an experimental model of atherosclerosis. Mice lacking MHC II expression only on B cells exhibited systemic shifts in germinal center and marginal zone B cell populations, leading to a reduced Ab response compared with littermate control animals. However, all populations were present and normal cholesterol uptake was detected in the plasma following high-fat diet treatment. In a second model, in which conditional expression of MHC II is limited only to B cells, showed similar overall cellularity characteristics compared with mice with complete MHC II deficiency. High-fat diet feeding showed no major changes in atherosclerotic plaque size or plaque cellular content in either conditional deletion or conditional expression approaches, compared with control animals. By testing the necessity and sufficiency of MHC II on B cells in the progression of atherosclerosis, we determine that MHC II on B cells does not directly regulate lesion development in murine models.

Activation of human brown adipose tissue by a ß3-adrenergic receptor agonist.

Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of ß3-adrenergic receptor (AR) agonists stimulates rodent BAT, but this activity has never been demonstrated in humans. Here we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a ß3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via (18)F-fluorodeoxyglucose ((18)F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 ± 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a ß3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease.