Understanding the Effects of Antipsychotics on Appetite Control

Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia and other psychoses. The effectiveness of the first generation (typical) APDs are hampered by so-called extrapyramidal side effects, and they have gradually been replaced by second (atypical) and third-generation APDs, with less extrapyramidal side effects and, in some cases, improved efficacy. However, the use of many of the current APDs has been limited due to their propensity to stimulate appetite, weight gain, and increased risk for developing type 2 diabetes and cardiovascular disease in this patient group. The mechanisms behind the appetite-stimulating effects of the various APDs are not fully elucidated, partly because their diverse receptor binding profiles may affect different downstream pathways. It is critical to identify the molecular mechanisms underlying drug-induced hyperphagia, both because this may lead to the development of new APDs, with lower appetite-stimulating effects but also because such insight may provide new knowledge about appetite regulation in general. Hence, in this review, we discuss the receptor binding profile of various APDs in relation to the potential mechanisms by which they affect appetite.publishedVersio

Incendiary Leptin

Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly expressed in the hypothalamus. Most scientific evidence points to leptin’s satiating effect being due to its dual capacity to promote the expression of anorexigenic neuropeptides and to reduce orexigenic expression in the hypothalamus. However, it has also been demonstrated that leptin can stimulate (i) thermogenesis in brown adipose tissue (BAT) and (ii) the browning of white adipose tissue (WAT). Since the demonstration of the importance of BAT in humans 10 years ago, its study has aroused great interest, mainly in the improvement of obesity-associated metabolic disorders through the induction of thermogenesis. Consequently, several strategies targeting BAT activation (mainly in rodent models) have demonstrated great potential to improve hyperlipidemias, hepatic steatosis, insulin resistance and weight gain, leading to an overall healthier metabolic profile. Here, we review the potential therapeutic ability of leptin to correct obesity and other metabolic disorders, not only through its satiating effect, but by also utilizing its thermogenic properties

Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice

Background and aims: Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. Methods: db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped. Results: db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT).Conclusion: Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiencyMinisterio de Ciencia y Universidades co-funded by the FEDER Program of EU (CD: BFU2017-87721; RN: RTI2018-099413-B-I00 and RED2018-102379-T; ML: RTI2018-101840-B-I00, PID2021-128145NB-I00 and PDC2022-133958-I00). “la Caixa” Foundation (ID100010434), under the agreement LCF/PR/HR19/52160022 (ML); EuroNanoMed III (RA & ML: EURONANOMED2019-050-ENAMEP); European Research Council (RN: ERC Synergy Grant-2019-WATCH-810331)S

Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1

Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand

Work and Welfare in the American States: Analyzing the Effects of the JOBS Program

This research seeks to determine whether the Job Opportunities and Basic Skills GOBS) program (established under the 1988 Family Support Act) was successful in reducing the number of welfare recipients among U.S. states for the period 1984 to 1996. Within the context of two theoretical perspectives-developmental and rational choice-we assess the impact of JOBS on AFDC participation rates using a pooled time-series design. At best, JOBS had a minimal effect. We estimate that states with higher proportions of their AFDC populations enrolled in JOBS programs had only slightly lower rates of participation in AFDC. Other forces were far more influential in reducing welfare participation. In particular, states with higher per capita income, lower female unemployment rates, lower poverty rates, and higher wages for low-paying jobs had the lowest welfare recipiency The AFDC participation rates of neighboring states had a significant effect, as well. The analysis showed that more generous AFDC benefits exerted strong upward pressure on a state's welfare rolls.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Les vésicules extracellulaires comme stratégie thérapeutique pour prévenir ou inverser l'obésité et ses complications métaboliques dans le domaine de la nanomédecine

Actual pharmacological therapies for treating obesity are limited. Promising results on decreasing mice body weight were obtained using a ventromedial nucleus hypothalamic (VMH) stereotaxic injection of a dominant negative isoform of AMPK (AMPK DN). However, DNA-mediated therapeutic potential is hampered by inadequate tissue specific delivery following a systemic injection - more adapted to a bedside approach -. Herein, we developed a nanobiomedicine approach using exosomes - nano-scaled endogenous vesicles containing lipids, proteins and nucleic acids - to deliver DNA in a hypothalamic specific way. Immature dendritic cells were used to generate non inflammatory exosomes. Exosome neuronal targeting aptitudes were achieved by constraining the dendritic cells to express Lamp2b, an exosomal protein, fused to the neuron-specific RVG peptide. Interestingly, DID-labelled Lamp2b-RVG exosomes were found into the mice brain following an intravenous injection. Isolated Lamp2b-RVG exosomes were then loaded by transfection-mediated techniques with AMPK DN under the control of a VMH specific promoter conferring double tissue expression specificity to the exosomes. AMPK DN-loaded exosomes induced a decrease of acetyl-CoA carboxylase phosphorylation in Neu2a neuronal cells in vitro. Furthermore, intravenously injected AMPK DN loaded exosomes induced a decrease of mice body weight following 6 days of treatment, demonstrating the potential of this nanobiomedicine approach.A ce jour, les thérapies anti-obésité restent limitées. De récente études ont fourni des résultats prometteurs en démontrant une diminution du poids de la souris via une injection stéréotaxique d’une forme dominante négative de l’AMPK (AMPK DN) directement dans le noyau ventromédial hypothalamique (VMH). Cependant, le potentiel thérapeutique de cette thérapie génique se voit entravé par une libération non spécifique de l’AMPK suite à une injection intraveineuse, plus adaptée à une approche clinique. Nous avons donc développé une approche de « nanobiomédecine » en utilisant des exosomes - nanovésicules contenant des lipides, des protéines et des acides nucléiques - pour délivrer l’AMPK DN spécifiquement au niveau du VMH. Des cellules dendritiques immatures ont été utilisées pour produire des exosomes non-inflammatoires. Pour permettre le ciblage spécifique du VMH par les exosomes, les cellules dendritiques ont été transfectées pour exprimer Lamp2b, une protéine exosomale, fusionnée au peptide de ciblage neuronal RVG. De façon intéressante, les exosomes Lamp2b-RVG ont été localisés au niveau du cerveau suite à une injection intraveineuse. Les exosomes Lamp2b-RVG ont ensuite été chargés par l’AMPK DN sous le contrôle d’un promoteur spécifique du VMH, apportant une double spéficité tissulaire aux exosomes. Les exosomes Lamp2b-RVG chargés avec l’AMPK DN induisaient une diminution de la phosphorylation de l’acetyl-CoA carboxylase dans des cellules Neu2A in vitro. De plus, l’injection intraveineuse d’exosomes Lamp2b-RVG chargés avec l’AMPK DN induisait une perte de poids de l’animal après 6 jours de traitement, démontrant le potentiel de cette approche de « nanobiomédecine »

Extracellular vesicles: Pharmacological modulators of the peripheral and central signals governing obesity

International audienc