Signaling through the nicotinic acetylcholine receptor in the liver protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature. Here, we identified a hepatic nonneuronal cholinergic signaling pathway required for metabolic adaptation to caloric overload. We found that cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) is highly expressed in hepatocytes of mice and humans. Further, CHRNA2 is activated by a subpopulation of local acetylcholine-producing macrophages during MASH development. The activation of CHRNA2 coordinates defensive programs against a broad spectrum of MASH-related pathogenesis, including steatosis, inflammation, and fibrosis. Hepatocyte-specific loss of CHRNA2 signaling accelerates the disease onset in different MASH mouse models. Activation of this pathway via pharmacological inhibition of acetylcholine degradation protects against MASH development. Our study uncovers a hepatic nicotinic cholinergic receptor pathway that constitutes a cell-autonomous self-defense route against prolonged metabolic stress and holds therapeutic potential for combatting human MASH.

Lactate oxidase/vSIRPα conjugates efficiently consume tumor-produced lactates and locally produce tumor-necrotic H2O2 to suppress tumor growth.

Aggressive tumor formation often leads to excessive anaerobic glycolysis and massive production and accumulation of lactate in the tumor microenvironment (TME). To significantly curb lactate accumulation in TME, in this study, lactate oxidase (LOX) was used as a potential therapeutic enzyme and signal regulatory protein α variant (vSIRPα) as a tumor cell targeting ligand. SpyCatcher protein and SpyTag peptide were genetically fused to LOX and vSIRPα, respectively, to form SC-LOX and ST-vSIRPα and tumor-targeting LOX/vSIRPα conjugates were constructed via a SpyCatcher/SpyTag protein ligation system. LOX/vSIRPα conjugates selectively bound to the CD47-overexpressing mouse melanoma B16-F10 cells and effectively consumed lactate produced by the B16-F10 cells, generating adequate amounts of hydrogen peroxide (H2O2), which induces drastic necrotic tumor cell death. Local treatments of B16-F10 tumor-bearing mice with LOX/vSIRPα conjugates significantly suppressed B16-F10 tumor growth in vivo without any severe side effects. Tumor-targeting vSIRPα may allow longer retention of LOX in tumor sites, effectively consuming surrounding lactate in TME and locally generating adequate amounts of cytotoxic H2O2 to suppress tumor growth. The approach restraining the local lactate concentration and H2O2 in TME using LOX and vSIRPα could offer new opportunities for developing enzyme/targeting ligand conjugate-based therapeutic tools for tumor treatment.

Investigating the effects of suicide exposure among a clinical sample of active duty service members.

Suicide exposure warrants further investigation as a risk factor for suicide among military service members. This study aimed to examine associations among suicide exposure, suicidal ideation (SI), and psychological symptoms in a clinical sample of service members (N = 1,565, 64.4% suicide-exposed) and identify how one's relationship with the deceased impacts suicidality and psychological health in exposed individuals. A secondary analysis of cross-sectional survey data was conducted. Generalized linear regression analyses were used to identify associations between suicide exposure and both current SI and psychological symptoms among all participants; the associations between suicide exposure characteristics and psychological symptoms were only examined among exposed individuals. Exposure was not significantly associated with higher SI, ß = .007, SE = .16, p = .965, but was associated with PTSD, ß = 1.60, SE = 0.49, p = .001; anxiety, ß = .68, SE = .31, p = .031; and insomnia symptoms, ß = .98, SE = .25, p < .001. Among participants who had been exposed, high/long impact of exposure was positively associated with SI, ß = 0.94, SE = .26, p < .001, and psychological symptoms, PTSD: ß = 2.32, SE = .77, p = .002; anxiety: ß = 1.39, SE = .50, p = .005; insomnia: ß = .96, SE = .39, p = .015. Results illustrate the significant issue of suicide exposure within the military and show consideration of suicide exposure as a potential risk factor for adverse psychological outcomes is warranted.

Internalization of muscularity and thinness ideals: Associations with body dissatisfaction, eating disorder symptoms, and muscle dysmorphic symptoms in at risk sexual minority men.

OBJECTIVE: In the tripartite influence model, appearance-ideal internalization is identified as a prominent risk factor for the development of body dissatisfaction and subsequent eating disorder (ED) behaviors. For men, prior research has emphasized the importance of both thin-ideal internalization and muscular-ideal internalization in explaining later ED behaviors and muscle dysmorphia (MD) symptoms. Previous research in heterosexual men has shown that the associations between muscular-ideal internalization and ED or MD symptoms may depend on whether the individual has also internalized the thin ideal. However, this interaction has not been examined in research with sexual minority men (SMM). METHOD: The current study collected self-report data from 452 at risk SMM (i.e., endorsed body dissatisfaction), with ages ranging from 18 to 35 years. Linear regression models were conducted to test the interaction effects between thinness and muscularity internalization on ED symptoms, MD behaviors, and general body dissatisfaction. Simple slopes and the Johnson-Neyman technique were used to investigate significant interaction terms. RESULTS: Thin- and muscular-ideal internalization were positively associated with muscular appearance intolerance and dietary restriction with no significant interaction. Muscular drive for size was highest when both muscularity internalization and thinness internalization were high. Muscular-ideal internalization was positively associated with both cognitive restraint and general body dissatisfaction, but only at lower levels of thinness internalization. DISCUSSION: Given the interacting association between thinness and muscularity internalization and aspects of body dissatisfaction, attitudes, and behavior, prevention and intervention programs for EDs and MDs in SMM should seek to dismantle both thinness and muscularity internalization. PUBLIC SIGNIFICANCE STATEMENT: Internalizing-or adopting as one's own-the ideal of a body with low body fat and high muscularity has been shown to lead to muscle dysmorphia and eating disorder symptoms in men. The current study examines whether the combination of thin-ideal and muscular-ideal internalization is associated with worse symptoms than either facet alone in sexual minority men. Treatment efforts in sexual minority men should address both types of internalization.

Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism.

Research focusing on adipose immunometabolism has been expanded from inflammation in white fat during obesity development to immune cell function regulating thermogenic fat, energy expenditure, and systemic metabolism. This opinion discusses our current understanding of how resident immune cells within the thermogenic fat niche may regulate whole-body energy homeostasis. Furthermore, various types of immune cells can synthesize acetylcholine (ACh) and regulate important physiological functions. We highlight a unique subset of cholinergic macrophages within subcutaneous adipose tissue, termed cholinergic adipose macrophages (ChAMs); these macrophages interact with beige adipocytes through cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) signaling to induce adaptive thermogenesis. We posit that these newly identified thermoregulatory macrophages may broaden our view of immune system functions for maintaining metabolic homeostasis and potentially treating obesity and metabolic disorders.

Directing ricin-based immunotoxins with targeting affibodies and KDEL signal peptide to cancer cells effectively induces apoptosis and tumor suppression.

The plant toxin ricin, especially its cytotoxic A chain (RTA), can be genetically engineered with targeting ligands to develop specific anti-cancer recombinant immunotoxins (RITs). Here, we used affibody molecules targeting two cancer biomarkers, the receptors HER2 and EGFR, along with the KDEL signal peptide to construct two cancer-specific ricin-based RITs, HER2Afb-RTA-KDEL and EGFRAfb-RTA-KDEL. The affibodies successfully provided target-specificity and subsequent receptor-mediated endocytosis and the KDEL signal peptide routed the RITs through the retrograde transport pathway, effectively delivering RTA to the cytosol as well as avoiding the alternate recycling pathway that typical cancer cells frequently have. The in vivo efficacy of RITs was enhanced by introducing the albumin binding domain (AlBD) to construct AlBD/HER2Afb/RTA-KDEL. Systemic administration of AlBD-containing RITs to tumor-bearing mice significantly suppressed tumor growth without any noticeable side-effects. Collectively, combining target-selective affibody molecules, a cytotoxic RTA, and an intracellularly designating peptide, we successfully developed cancer-specific and efficacious ricin-based RITs. This approach can be applied to develop novel protein-based "magic bullets" to effectively suppress tumors that are resistant to conventional anti-cancer drugs.

TRAIL & EGFR affibody dual-display on a protein nanoparticle synergistically suppresses tumor growth.

The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer drug candidate because it selectively binds to the proapoptotic death receptors, which are frequently overexpressed in a wide range of cancer cells, subsequently inducing strong apoptosis in these cells. However, the therapeutic benefit of TRAIL has not been clearly proven, mainly because of its poor pharmacokinetic characteristics and frequent resistance to its application caused by the activation of a survival signal via the EGF/epidermal growth factor receptor (EGFR) signaling pathway. Here, a lumazine synthase protein cage nanoparticle isolated from Aquifex aeolicus (AaLS) was used as a multiple ligand-displaying nanoplatform to display polyvalently both TRAIL and EGFR binding affibody molecules (EGFRAfb) via a SpyTag/SpyCatcher protein-ligation system, to form AaLS/TRAIL/EGFRAfb. The dual-ligand-displaying AaLS/TRAIL/EGFRAfb exhibited a dramatically enhanced cytotoxicity on TRAIL-resistant and EGFR-overexpressing A431 cancer cells in vitro, effectively disrupting the EGF-mediated EGFR survival signaling pathway by blocking EGF/EGFR binding as well as strongly activating both the extrinsic and intrinsic apoptotic pathways synergistically. The AaLS/TRAIL/EGFRAfb selectively targeted A431 cancer cells in vitro and actively reached the tumor sites in vivo. The A431 tumor-bearing mice treated with AaLS/TRAIL/EGFRAfb exhibited a significant suppression of the tumor growth without any significant side effects. Collectively, these findings showed that the AaLS/TRAIL/EGFRAfb could be used as an effective protein-based therapeutic for treating EGFR-positive cancers, which are difficult to manage using mono-therapeutic approaches.

The Adipose Tissue Macrophages Central to Adaptive Thermoregulation.

White fat stores excess energy, and thus its excessive expansion causes obesity. However, brown and beige fat, known as adaptive thermogenic fat, dissipates energy in the form of heat and offers a therapeutic potential to counteract obesity and metabolic disorders. The fat type-specific biological function is directed by its unique tissue microenvironment composed of immune cells, endothelial cells, pericytes and neuronal cells. Macrophages are major immune cells resident in adipose tissues and gained particular attention due to their accumulation in obesity as the primary source of inflammation. However, recent studies identified macrophages' unique role and regulation in thermogenic adipose tissues to regulate energy expenditure and systemic energy homeostasis. This review presents the current understanding of macrophages in thermogenic fat niches with an emphasis on discrete macrophage subpopulations central to adaptive thermoregulation.

CHRNA2: a new paradigm in beige thermoregulation and metabolism.

The contribution of thermogenic adipocytes to maintain systemic metabolic homeostasis has been increasingly appreciated in recent years. It is now recognized that different types (e.g., brown, beige) and subtypes of thermogenic adipocytes may arise from various developmental origins. In addition to the adrenergic pathway, other signals can activate thermogenesis, including paracrine communication between immune cells within the adipose tissue niche and thermogenic adipocytes. In this opinion article we highlight the recently discovered beige-selective signaling between acetylcholine from immune cells and cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) in activated beige adipocytes. We present our current knowledge of how this previously unrecognized adipose non-neuronal cholinergic signaling pathway mediates beige thermoregulation, and discuss its impact on whole-body fitness and its therapeutic potential as a novel target for combating metabolic disease.

Acetylcholine-synthesizing macrophages in subcutaneous fat are regulated by ß2 -adrenergic signaling.

Non-neuronal cholinergic signaling, mediated by acetylcholine, plays important roles in physiological processes including inflammation and immunity. Our group first discovered evidence of non-neuronal cholinergic circuitry in adipose tissue, whereby immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis. Here, we reveal that macrophages are the cellular protagonists responsible for secreting acetylcholine to regulate thermogenic activation in subcutaneous fat, and we term these cells cholinergic adipose macrophages (ChAMs). An adaptive increase in ChAM abundance is evident following acute cold exposure, and macrophage-specific deletion of choline acetyltransferase (ChAT), the enzyme for acetylcholine biosynthesis, impairs the cold-induced thermogenic capacity of mice. Further, using pharmacological and genetic approaches, we show that ChAMs are regulated via adrenergic signaling, specifically through the ß2 adrenergic receptor. These findings demonstrate that macrophages are an essential adipose tissue source of acetylcholine for the regulation of adaptive thermogenesis, and may be useful for therapeutic targeting in metabolic diseases.

Appearance-ideal internalization, body dissatisfaction, and suicidality among sexual minority men.

Sexual minority men (SMM) are disproportionately at risk for suicidality. Furthermore, SMM are at elevated risk for appearance-ideal internalization and body dissatisfaction, which are both associated with suicidality. Theoretical recommendations suggest including interaction terms between appearance-ideal internalization and body dissatisfaction when examining deleterious health outcomes. To test these interactions and examine whether appearance-ideal internalization or body dissatisfaction impart greater suicidality, the current study analyzed associations between specific forms of appearance-ideal internalization and suicidality among SMM, and whether body dissatisfaction moderated these associations. Participants were 171 SMM recruited for an eating disorder prevention program. Analyses examined the association between thin and muscular-ideal internalization with count of suicide risk, with body fat and muscularity dissatisfaction moderating these associations. Zero-inflated Poisson regressions revealed that the association between thin-ideal internalization and suicide risk was moderated by body fat dissatisfaction, such that thin-ideal internalization was associated with increased suicide risk at high levels of body fat dissatisfaction. Muscularity concerns were not significantly associated with suicidality, suggesting that thinness concerns may be more salient than muscularity for suicidality among SMM. Future research should replicate findings among larger SMM samples and extend the current design into non-SMM samples to examine if results generalize to other vulnerable populations.

Target-switchable Gd(III)-DOTA/protein cage nanoparticle conjugates with multiple targeting affibody molecules as target selective T1 contrast agents for high-field MRI.

Magnetic resonance imaging (MRI) is a non-invasive in vivo imaging tool, providing high enough spatial resolution to obtain both the anatomical and the physiological information of patients. However, MRI generally suffers from relatively low sensitivity often requiring the aid of contrast agents (CA) to enhance the contrast of vessels and/or the tissues of interest from the background. The targeted delivery of diagnostic probes to the specific lesion is a powerful approach for early diagnosis and signal enhancement leading to the effective treatment of various diseases. Here, we established targeting ligand switchable nanoplatforms using lumazine synthase protein cage nanoparticles derived from Aquifex aeolicus (AaLS) by genetically introducing the SpyTag peptide (ST) to the C-terminus of the AaLS subunits to form an ST-displaying AaLS (AaLS-ST). Conversely, multiple targeting ligands were constructed by genetically fusing SpyCatcher protein (SC) to either HER2 or EGFR targeting affibody molecules (SC-HER2Afb or SC-EGFRAfb). Gd(III)-DOTA complexes were chemically attached to the AaLS-ST and the external surface of the Gd(III)-DOTA conjugated AaLS-ST (Gd(III)-DOTA-AaLS-ST) were successfully decorated with either the HER2Afb or the EGFRAfb. The resulting Gd(III)-DOTA-AaLS/HER2Afb and Gd(III)-DOTA-AaLS/EGFR2Afb exhibited high r1 relaxivity values of 57 and 25 mM-1 s-1 at 1.4 and 7 T, respectively, which were 10-fold or higher than those of the clinically used Dotarem. Their target-selective contrast enhancements were confirmed with in vitro cell-based MRI scans and the in vivo MR imaging of tumor-bearing mouse models at 7 T. A target-switchable AaLS-based nanoplatform that was developed in this study might serve as a promising T1 CA developing platform at a high magnetic field to detect various tumor sites in a target-specific manner in future clinical applications.

Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.

The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of C. elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the invertebrate homolog of norepinephrine, by regulating the energy sensor AMPK through a Gq-PLCß-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain-gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.

Sexual orientation and gender identity disparities in co-occurring depressive symptoms and probable substance use disorders in a national cohort of young adults.

This study examined sexual orientation and gender identity differences in co-occurring depressive symptoms and substance use disorders (SUDs) among young adults in the Growing Up Today Study national cohort (n = 12,347; ages 20-35; 93% non-Hispanic white). Self-administered questionnaires assessed recent co-occurring depressive symptoms and probable nicotine dependence, alcohol use disorder, and drug use disorder. Multinomial logistic regressions with generalized estimating equations quantified differences in prevalences of depressive symptoms only, SUDs only, and co-occurrence, among sexual minorities (mostly heterosexual; lesbian, gay, and bisexual [LGB]) compared to completely heterosexual participants, and gender minorities compared to cisgender participants. Analyses stratified by sex assigned at birth revealed sexual minorities evidenced greater odds of co-occurrence than their completely heterosexual counterparts (assigned female AORs: 3.11-9.80, ps < 0.0001; assigned male AORs: 2.90-4.87, ps < 0.001). Sexual orientation differences in co-occurrence were pronounced among LGB participants assigned female at birth who evidenced nearly 10 times the odds of co-occurring depressive symptoms with nicotine dependence and drug use disorders than did heterosexual participants assigned female at birth. Relationships between gender identity and co-occurrence were generally weaker, possibly due to low power. Gender minorities assigned male at birth, however, evidenced greater odds of co-occurring depressive symptoms and alcohol use disorders (AOR 2.75, p = 0.013) than their cisgender counterparts. This study adds to the limited research quantifying sexual orientation or gender identity differences in recent co-occurring depressive symptoms and SUDs among young adults and suggests sexual and gender minority young adults should be prioritized in prevention and treatment of co-occurring depression and SUDs.

A critical role for hepatic protein arginine methyltransferase 1 isoform 2 in glycemic control.

Appropriate control of hepatic gluconeogenesis is essential for the organismal survival upon prolonged fasting and maintaining systemic homeostasis under metabolic stress. Here, we show protein arginine methyltransferase 1 (PRMT1), a key enzyme that catalyzes the protein arginine methylation process, particularly the isoform encoded by Prmt1 variant 2 (PRMT1V2), is critical in regulating gluconeogenesis in the liver. Liver-specific deletion of Prmt1 reduced gluconeogenic capacity in cultured hepatocytes and in the liver. Prmt1v2 was expressed at a higher level compared to Prmt1v1 in hepatic tissue and cells. Gain-of-function of PRMT1V2 clearly activated the gluconeogenic program in hepatocytes via interactions with PGC1α, a key transcriptional coactivator regulating gluconeogenesis, enhancing its activity via arginine methylation, while no effects of PRMT1V1 were observed. Similar stimulatory effects of PRMT1V2 in controlling gluconeogenesis were observed in human HepG2 cells. PRMT1, specifically PRMT1V2, was stabilized in fasted liver and hepatocytes treated with glucagon, in a PGC1α-dependent manner. PRMT1, particularly Prmt1v2, was significantly induced in the liver of streptozocin-induced type 1 diabetes and high fat diet-induced type 2 diabetes mouse models and liver-specific Prmt1 deficiency drastically ameliorated diabetic hyperglycemia. These findings reveal that PRMT1 modulates gluconeogenesis and mediates glucose homeostasis under physiological and pathological conditions, suggesting that deeper understanding how PRMT1 contributes to the coordinated efforts in glycemic control may ultimately present novel therapeutic strategies that counteracts hyperglycemia in disease settings.

Adrenergic-Independent Signaling via CHRNA2 Regulates Beige Fat Activation.

Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting ß-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic beige fat, a subpopulation of beige adipocytes mediated by GABPα emerging in the absence of ß-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in beige fat biogenesis and energy homeostasis.

Stress, Coping, and Context: Examining Substance Use Among LGBTQ Young Adults With Probable Substance Use Disorders.

OBJECTIVE: The authors qualitatively examined how lesbian, gay, bisexual, transgender, and queer (LGBTQ) young adults with probable substance use disorders conceptualized their substance use vis-à-vis their LGBTQ identities. METHODS: Individual, in-depth, semistructured interviews were conducted with 59 LGBTQ young adults (ages 21-34) who were participants in a larger longitudinal cohort study and who met criteria for a probable substance use disorder. Data were analyzed via iterative, thematic analytic processes. RESULTS: Participants' narratives highlighted processes related to minority stress that shape substance use, including proximal LGBTQ stressors (e.g., self-stigma and expectations of rejection) and distal LGBTQ stressors (e.g., interpersonal and structural discrimination) and associated coping. Participants also described sociocultural influences, including the ubiquitous availability of substances within LGBTQ social settings, as salient contributors to their substance use and development of substance use disorders. Participants who considered themselves transgender or other gender minorities, all of whom identified as sexual minorities, described unique stressors and coping at the intersection of their minority identities (e.g., coping with two identity development and disclosure periods), which shaped their substance use over time. CONCLUSIONS: Multilevel minority stressors and associated coping via substance use in adolescence and young adulthood, coupled with LGBTQ-specific sociocultural influences, contribute to the development of substance use disorders among some LGBTQ young adults. Treatment providers should address clients' substance use vis-à-vis their LGBTQ identities and experiences with related stressors and sociocultural contexts and adopt culturally humble and LGBTQ-affirming treatment approaches. Efforts to support LGBTQ youths and young adults should focus on identifying ways of socializing outside of substance-saturated environments.

Sexual orientation and gender identity disparities in substance use disorders during young adulthood in a United States longitudinal cohort.

BACKGROUND: This study examined associations of sexual orientation and gender identity with prevalence of substance use disorders (SUDs) and co-occurring multiple SUDs in the past 12-months during young adulthood in a United States longitudinal cohort. METHODS: Questionnaires self-administered in 2010 and 2015 assessed probable past 12-month nicotine dependence, alcohol abuse and dependence, and drug abuse and dependence among 12,428 participants of an ongoing cohort study when they were ages 20-35 years. Binary or multinomial logistic regressions using generalized estimating equations were used to estimate differences by sexual orientation and gender identity in the odds of SUDs and multiple SUDs, stratified by sex assigned at birth. RESULTS: Compared with completely heterosexuals (CH), sexual minority (SM; i.e., mostly heterosexual, bisexual, lesbian/gay) participants were generally more likely to have a SUD, including multiple SUDs. Among participants assigned female at birth, adjusted odds ratios (AORs) for SUDs comparing SMs to CHs ranged from 1.61 to 6.97 (ps<.05); among participants assigned male at birth, AORs ranged from 1.30 to 3.08, and were statistically significant for 62% of the estimates. Apart from elevated alcohol dependence among gender minority participants assigned male at birth compared with cisgender males (AOR: 2.30; p < .05), gender identity was not associated with prevalence of SUDs. CONCLUSIONS: Sexual and gender minority (SGM) young adults disproportionately evidence SUDs, as well as co-occurring multiple SUDs. Findings related to gender identity and bisexuals assigned male at birth should be interpreted with caution due to small sample sizes. SUD prevention and treatment efforts should focus on SGM young adults.

Effects of familial and non-familial warmth during childhood and adolescence on sexual-orientation disparities in alcohol use trajectories and disorder during emerging adulthood.

BACKGROUND: We investigated sexual-orientation differences in typologies of self-reported familial and non-familial warmth in childhood (before age 11) and adolescence (ages 11-17); and tested whether warmth explained sexual minority emerging adults' (ages 18-25) heightened odds of having heavier alcohol use trajectories (AUTs) and heightened risk for past-year alcohol use disorder (AUD) compared to completely heterosexuals. METHODS: Using self-reported data from the U.S.-based Growing Up Today Study cohort, latent class analyses identified typologies of familial and non-familial warmth during childhood and adolescence. Multivariable regression models tested our objectives. RESULTS: Six warmth classes emerged, including: High-High (i.e., high familial and high non-familial warmth, respectively); High-Moderate; Moderate-Moderate; Moderate-Occasional; Occasional-Occasional; and Low-Low. Among women, sexual minorities had higher odds than completely heterosexuals of being in the Moderate-Moderate, Moderate-Occasional, and Occasional-Occasional versus the High-High warmth class. There were not significant associations between sexual orientation and warmth classes for men. Lower warmth classes were generally associated with greater past-year AUD, and mediated heightened disparities in AUD for sexual minority women versus completely heterosexual women (4.3% mediated), but not among men. Warmth classes were generally unassociated with AUTs, and did not mediate sexual-orientation differences in AUTs. CONCLUSIONS: Lower warmth was associated with greater alcohol-related problems, but not alcohol use itself. Warmth explained a small proportion of AUD disparities for sexual minority women-but not for men.

Protein Arginine Methyltransferase 1 Interacts With PGC1α and Modulates Thermogenic Fat Activation.

Protein arginine methyltransferases (PRMTs) are enzymes that regulate the evolutionarily conserved process of arginine methylation. It has been reported that PRMTs are involved in many metabolic regulatory pathways. However, until now, their roles in adipocyte function, especially browning and thermogenesis, have not been evaluated. Even though Prmt1 adipocyte-specific-deleted mice (Prmt1fl/flAQcre) appeared normal at basal level, following cold exposure or ß-adrenergic stimulation, impaired induction of the thermogenic program was observed in both the interscapular brown adipose tissue and inguinal white adipose tissue of Prmt1fl/flAQcre mice compared with littermate controls. Different splicing variants of Prmt1 have been reported. Among them, PRMT1 variant 1 and PRMT1 variant 2 (PRMT1V2) are well conserved between humans and mice. Both variants contribute to the activation of thermogenic fat, with PRMT1V2 playing a more dominant role. Mechanistic studies using cultured murine and human adipocytes revealed that PRMT1V2 mediates thermogenic fat activation through PGC1α, a transcriptional coactivator that has been shown to play a key role in mitochondrial biogenesis. To our knowledge, our data are the first to demonstrate that PRMT1 plays a regulatory role in thermogenic fat function. These findings suggest that modulating PRMT1 activity may represent new avenues to regulate thermogenic fat and mediate energy homeostasis. This function is conserved in human primary adipocytes, suggesting that further investigation of this pathway may ultimately lead to therapeutic strategies against human obesity and associated metabolic disorders.