Anti-obesity Therapy Research Articles

Simple and rapid voltammetric method for the detection of the synthetic adulterant fluoxetine in weight loss products

In the global obesity pandemic, the demand for healthy products that provide weight loss is increasing. However, undeclared adulterants are commonly added to increase their performance and the development of rapid methods for detecting these compounds is fundamentally important. In this work, it was demonstrated that an electrochemical technique (square wave voltammetry) using boron-doped diamond (BDD) as the working electrode can be used for rapid screening and quantification of the doping substance fluoxetine (FLU) in samples like thermogenic supplements, compounded drugs, and weight loss herbal medicines. Fast screening of FLU is possible after easy sample dilution in a supporting electrolyte solution (0.1 mol L-1 H2SO4). In addition to the simplicity and low cost of the proposed method, adequate analytical characteristics in terms of limits of detection (0.1 mg L-1), linear range (1 to 50 mg L-1; r = 0.993), and recovery values (104 ± 6 %) were obtained. These results suggest that the method has great potential as a simple and fast screening test to detect FLU in natural products for anti-obesity therapy.

Obesity as a Neuroendocrine Reprogramming.

Obesity represents a health problem resulting from a broken balance between energy intake and energy expenditure leading to excess fat accumulation. Elucidating molecular and cellular pathways beyond the establishment of obesity remains the main challenge facing the progress in understanding obesity and developing its treatment. Within this context, this opinion presents obesity as a reprogrammer of selected neurological and endocrine patterns in order to adapt to the new metabolic imbalance represented by obesity status. Indeed, during obesity development, the energy balance is shifted towards increased energy storage, mainly but not only, in adipose tissues. These new metabolic patterns that obesity represents require changes at different cellular and metabolic levels under the control of the neuroendocrine systems through different regulatory signals. Therefore, there are neuroendocrine changes involving diverse mechanisms, such as neuroplasticity and hormonal sensitivity, and, thus, the modifications in the neuroendocrine systems in terms of metabolic functions fit with the changes accompanying the obesity-induced metabolic phenotype. Such endocrine reprogramming can explain why it is challenging to lose weight once obesity is established, because it would mean to go against new endogenous metabolic references resulting from a new “setting” of energy metabolism-related neuroendocrine regulation. Investigating the concepts surrounding the classification of obesity as a neuroendocrine reprogrammer could optimize our understanding of the underlying mechanisms and, importantly, reveal some of the mysteries surrounding the molecular pathogenesis of obesity, as well as focusing the pharmacological search for antiobesity therapies on both neurobiology synaptic plasticity and hormonal interaction sensitivity.

Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress.

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.

Enhanced brain biodistribution of Ginsenoside Rg1 based self-nanoemulsifying drug delivery system to ameliorate metabolic syndromes and keep homeostatic balance

The aim of the study was to develop and characterize Ginsenoside Rg1 (GRg1) based self-nanoemulsifying system (SNES) to enhance its solubility, oral bioavailability and brain targeting. The anti-obesity efficacy and safety assessment compared to orlistat were also carried out. Solubility of GRg1 in various vehicles was carried out to recognize the optimum concentration of the component of SNES; pseudo-ternary phase diagrams were constructed to recognize the self-emulsifying area. Thermo stability test was performed to check the stability of the formulations. The stable ones were characterized for particle size, zeta potential, cloudiness, surface morphology, rheological properties, drug dissolution, ex vivo permeation as well as brain distribution. Anti-obesity efficacy of the optimized formula in comparison to orlistat was done using obese induced model in rats. The optimized formulations gave a spontaneous and stable nanoemulsion upon diluting with water, with optimum polydispersity index and negative zeta potential. The results revealed that SNES as a drug vehicle could improve the dissolution and absorption of GRg1. The results demonstrated that the GRg1 based SNES could ameliorate metabolic syndromes and keep homeostatic balances as it could maintain the lipid profile and lipase level. It also could reduce the oxidative stress markers, depress the appetite, and prevent hepatocyte degradation. In conclusion using SNES as carrier to GRg1 could avoid the first pass and increased its viability in blood and consequently targeted it to the brain in higher concentration compared to conventional extract. Moreover, it can be used as a promising antiobesity therapy to prevent metabolic and energy dysfunction of orlistat.

Contrasting Anti-obesity Effects of Smectite Clays and Mesoporous Silica in Sprague-Dawley Rats.

Porous colloids have been shown to exert unique bioactivities for mediating lipid (fat) metabolism and thereby offer significant potential as anti-obesity therapies. In this study, we compare the capacity for two classes of colloids, that is, smectite clays (Laponite XLG, LAP; montmorillonite, MMT) and mesoporous silica (SBA-15 ordered silica; MPS), to impede intestinal lipid hydrolysis and provoke lipid and carbohydrate excretion through adsorption within their particle matrices. A two-stage in vitro gastrointestinal lipolysis model revealed the capacity for both smectite clays and MPS to inhibit the rate and extent of lipase-mediated digestion under simulated fed state conditions. Each system adsorbed more than its own weight of organic media (i.e., lipid and carbohydrates) after 60 min lipolysis, with MMT adsorbing >10% of all available organics through the indiscriminate adsorption of fatty acids and glycerides. When co-administered with a high-fat diet (HFD) to Sprague-Dawley rats, treatment with MMT and MPS significantly reduced normalized rodent weight gain compared to a negative control, validating their potential to restrict energy intake and serve as anti-obesity therapies. However, in vitro-in vivo correlations revealed poor associations between in vitro digestion parameters and normalized weight gain, indicating that additional/alternate anti-obesity mechanisms may exist in vivo, while also highlighting the need for improved in vitro assessment methodologies. Despite this, the current findings emphasize the potential for porous colloids to restrict weight gain and promote anti-obesity effects to subjects exposed to a HFD and should therefore drive the development of next-generation food-grade biomaterials for the treatment and prevention of obesity.

A safe and efficient bioactive citrate-lysine/miRNA33 agonist nanosystem for high fat diet-induced obesity therapy

The increased prevalence of obesity is recognized as a serious public health problem affecting millions of people. Although some anti-obesity drugs are currently licensed for use, these drugs involve diverse side effects such as diarrhea, vomiting, and low efficiency. Here we developed a safe and efficient biomaterials-based anti-obesity nanosystem (PCG-EPL/miR33agonist), which was formed with poly (citric acid)-glycerol-polylysine (PCG-EPL) and miR33 agonist by self-assembly. The PCG-EPL could efficiently load, protect and deliver the miR33 agonist into the adipocytes and decreased the obesity-related IL-1β expression in adipocytes in vitro. The high-fat diet induced obese rat model experiment showed that the PCG-EPL/miR33agonist via caudal vein injection effectively reduced the body weight by enhancing lipid metabolism and decreasing the inflammatory factors expressions (IL-1β, TNF-α and IL-6) in vivo, without suppressing the appetite of rat. Compared with the obese mice, mice in PCG-EPL/miR33 had higher average food intake but lower energy conversion rate. PCG-EPL/miR33agonist significantly inhibited the growth of adipocytes. Noteworthy, this weight loss strategy is not only safe and efficient, but also does not need diet control. Thus, PCG-EPL may serve as an ideal platform for RNA drug delivery in anti-obesity therapy, especially for those who need to lose weight but unable to autonomously control their diet.

Addition of Probiotics to Anti-Obesity Therapy by Percutaneous Electrical Stimulation of Dermatome T6. A Pilot Study.

Obesity is becoming a pandemic and percutaneous electrical stimulation (PENS) of dermatome T6 has been demonstrated to reduce stomach motility and appetite, allowing greater weight loss than isolated hypocaloric diets. However, modulation of intestinal microbiota could improve this effect and control cardiovascular risk factors. Our objective was to test whether addition of probiotics could improve weight loss and cardiovascular risk factors in obese subjects after PENS and a hypocaloric diet. A pilot prospective study was performed in patients (n = 20) with a body mass index (BMI) > 30 kg/m2. Half of them underwent ten weeks of PENS in conjunction with a hypocaloric diet (PENS-Diet), and the other half was treated with a PENS-Diet plus multistrain probiotics (L. plantarum LP115, B. brevis B3, and L. acidophilus LA14) administration. Fecal samples were obtained before and after interventions. The weight loss and changes in blood pressure, glycemic and lipid profile, and in gut microbiota were investigated. Weight loss was significantly higher (16.2 vs. 11.1 kg, p = 0.022), whereas glycated hemoglobin and triglycerides were lower (−0.46 vs. −0.05%, p = 0.032, and −47.0 vs. −8.5 mg/dL, p = 0.002, respectively) in patients receiving PENS-Diet + probiotics compared with those with a PENS-Diet. Moreover, an enrichment of anti-obesogenic bacteria, including Bifidobacterium spp, Akkermansia spp, Prevotella spp, and the attenuation of the Firmicutes/Bacteroidetes ratio were noted in fecal samples after probiotics administration. In obese patients, the addition of probiotics to a PENS intervention under a hypocaloric diet could further improve weight loss and glycemic and lipid profile in parallel to the amelioration of gut dysbiosis.

Pyrazolone derivative C29 protects against HFD-induced obesity in mice via activation of AMPK in adipose tissue.

Beige adipocytes have been considered as a potential strategy in anti-obesity therapy because of its thermogenic capacity. AMP-activated protein kinase (AMPK) plays important roles in regulating adipose tissue function. C29 is a novel pyrazolone derivative with AMPK activity. In the current study, we investigated the role of C29 in the regulation of thermogenesis using differentiated adipocytes and diet-induced obese mice, and explored the mechanisms that might be involved in energy expenditure via adipocyte AMPK activation. We showed that treatment with C29 (2.5-10 μM) concentration-dependently increased thermogenesis in differentiated preadipocytes separated from inguinal white adipose tissue (iWAT), evidenced by increased expression levels of thermogenesis markers such as Ucp1, Pgc-1α, Dio2, Prdm16, Cox7a1, Cox8b, Elovl3, and Cidea, fatty acid oxidation (FAO) genes including Cpt1a, Lcad and Pparα, as well as beige-selective genes such as Cd137, Tmem26, Slc27a1, and Tbx1. In high-fat diet (HFD)-fed mice, oral administration of C29 (30 mg·kg-1·day-1) for 9 weeks alleviated HFD-induced obesity, promoted energy expenditure and modulated iWAT browning. However, these effects were not observed in adipose-specific AMPKα1/α2 knockout (AKO) mice following C29 administration. Together, this study demonstrates that C29 regulates energy balance via adipocyte AMPK. Our findings show that the discovery of AMPK activators that specifically target adipose tissue may have therapeutic potential for treating obesity-related metabolic diseases.

Computational Drug Repurposing Approach to Identify Potential Fatty Acid-Binding Protein-4 Inhibitors to Develop Novel Antiobesity Therapy.

Obesity is a chronic human disorder caused by multiple factors, causing excessive accumulation of fat because of the disparity in take of energy intake with respect to its expenditure. Genetic, environmental, and behavioral factors are having a crucial role in its pathogenesis. Fatty acid-binding protein (FABP) is a superfamily that was involved in the transportation, metabolism, and storage of lipids. The experimental studies have revealed that there is a significant rise in the fatty acid-binding protein-4 (FABP4) expression, and plasma concentration in obese and its downregulation or inhibition can be a potential drug target for obesity. Repurposing of drugs is a trending method for the identification of the newer pharmacological action of an established drug molecule having initially approved indication. It is a cost-effective and economical approach for the development of alternative therapies for existing dreadful diseases in quick succession. Thus, the in silico drug repurposing technique is a highly effective approach for identifying an existing drug molecule having an antiobesity therapeutic activity against the human FABP4, and Floxacillin was selected as safe and effective drug for candidates for developing an antiobesity therapy.

Maternal high-fat diet up-regulates type-1 cannabinoid receptor with estrogen signaling changes in a sex- and depot- specific manner in white adipose tissue of adult rat offspring.

Obesity and high-fat (HF) diet are associated with over activation of the endocannabinoid system (ECS). We have demonstrated that maternal HF diet induces early obesity and modulates cannabinoid signaling in visceral (VIS) and subcutaneous (SUB) white adipose tissue (WAT) in weanling rat offspring. We hypothesized that perinatal maternal HF diet would program the expression of ECS in adipose tissue in a long-term way in parallel to alterations in epigenetic markers and sex hormone signaling. Progenitor female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8weeks before mating, gestation, and lactation. All pups were weaned to C diet and they were euthanized at 180days old. Maternal HF diet induced overweight and increased SUB WAT mass of male and female adult offspring. Maternal HF diet induced hypertrophy of VIS and SUB adipocytes only in female offspring associated with increased type 1 cannabinoid receptor protein (CB1) and mRNA (Cnr1) levels. These changes were associated with increased estrogen receptor α binding to Cnr1 promoter in SUB WAT of adult female offspring, which may contribute to higher expression of Cnr1. Increased CB1 signaling in adipose tissue might contribute to higher adiposity programmed by maternal HF diet because endocannabinoids stimulate the accumulation of fat in the adipose tissue. Our findings provide molecular insights into sex-specific targets for anti-obesity therapies based on the endocannabinoid system.

Brain-derived neurotrophic factor modulates mitochondrial dynamics and thermogenic phenotype on 3T3-L1 adipocytes

Obesity is a growing threat. In recent years, the finding of functional brown adipose tissue (BAT) in adult humans implemented the studies of anti-obesity therapies based on triggering energy expenditure. The activation of BAT thermogenesis and the recruitment of brite (brown-in-white) adipocytes are under noradrenergic control. Brain-derived neurotrophic factor (BDNF), if centrally administered, enhances thermogenesis through sympathetic activation, but its direct effect on adipocytes is still unclear. The phenotypic change from fat storing to thermogenic adipocytes is recognized by the presence of multilocular lipid droplets (LDs) and fissed mitochondria that tend to surround LDs, maximizing the efficiency of fatty acid release for thermogenesis. BDNF treatment on differentiated 3T3-L1 adipocytes was compared to negative (CTRL) and positive (norepinephrine, NE) controls. BDNF significantly increased small globular mitochondria percentage (>150% CTRL), while the area surface and elongation index of branched tubules were respectively 55% and 10% lower than NE. Canonical discriminant analysis of mitochondria morphological data clearly separated differentially treated cells with 85% of the total variance. The expression of brown markers and mitochondrial dynamic genes was significantly affected by BDNF. Investigating the pathways involved in adipocyte BDNF stimulation could clarify its role in thermogenesis and its possible local regulation.

SUN-LB102 Development of a Conceptual Model to Present the Impacts of Obesity on Physical Functioning

Background. Obesity is a chronic disease with a significant negative impact on health-related quality of life (HRQoL) and specifically, physical functioning, including the ability to complete activities of daily living (ADLs). Weight loss based on lifestyle management (e.g. diet, exercise), surgery, and pharmacotherapy can improve physical functioning; however, there is a need for further qualitative research to support the content validity of patient-reported outcome (PRO) measures for use in clinical studies of obesity and thus inform regulatory decision-making. Objective. To explore the impacts of obesity on physical functioning and develop a conceptual model (a visual representation of the concepts of importance and relevance to the experience of living with obesity) to ultimately support the content validity of PRO measures.Methods. Qualitative semi-structured interviews were conducted in the United States with individuals who have overweight and obesity (Body Mass Index [BMI] ≥ 27.0 kg/m2) with a history of at least one unsuccessful dietary effort to lose body weight. Recruitment quotas targeted a sample with diverse demographic and clinical characteristics, including participants with and without diabetes. Experienced qualitative interviewers used open-ended questions to elicit spontaneous reports of the impact of obesity on individuals’ daily lives, and specific probing questions to explore impacts on physical functioning. Interviews were audio-recorded, transcribed and analyzed using thematic techniques. Results. A total of 33 participants were interviewed (mean BMI of 37.6 kg/m2 [27.4 kg/m2 to 56.6 kg/m2]; mean age of 45 years [19 to 81 years]). The sample included a mix of races (Caucasian: n=12, 36%), education completed (high school: n=17, 51%) and split of gender (female: n=16, 48%). During development of the conceptual model, two separate domains were identified to group the reported impacts on physical functioning: ‘Mobility/Movement’ and ‘ADLs’. The most frequently reported impacts related to Mobility/Movement were ‘running’ (n=31/33, 94%), ‘bending’ (n=27/33, 82%), ‘walking’ (n=26/33, 79%), ‘difficulty standing for prolonged periods’ (n=22/33, 67%), and ‘lifting’ (n=19/33, 58%). All participants reported effects on some aspect of physical functioning, which were often characterized in terms of their direct impact on ADLs such as ‘household chores’ (n=21/33, 64%). Conclusions. The conceptual model will serve as a basis to identify fit-for-purpose PRO measures with strong content validity to evaluate the impact of anti-obesity therapies on physical functioning in future clinical studies. Obesity has a consistent and significant impact on physical functioning, leading to limitations in various aspects of mobility and affecting an individual’s ability to carry out specific daily activities.

Anti-obesity therapy with peripheral CB1 blockers: from promise to safe(?) practice.

Pharmacological blockers of the cannabinoid receptor type-1 (CB1) have been considered for a long time as the holy grail of obesity pharmacotherapy. These agents were hastily released in the clinical setting, due to their clear-cut therapeutic efficacy. However, the first generation of these drugs, which were able to target both the brain and peripheral tissues, had serious neuropsychiatric effects, leading authorities to ban their clinical use. New peripherally restricted CB1 blockers, characterized by low brain penetrance, have been developed over the past 10 years. In preclinical studies, these molecules seem to overcome the neuropsychiatric negative effects previously observed with brain-penetrant CB1 inhibitors, while retaining or even outperforming their efficacy. The mechanisms of action of these peripherally restricted compounds are only beginning to emerge, and a balanced discussion of the risk/benefits ratio associated to their possible clinical use is urgently needed, in order to avoid repeating past mistakes. Here, we will critically discuss the advantages and the possible hidden threats associated with the use of peripheral CB1 blockers for the pharmacotherapy of obesity and its associated metabolic complications. We will address whether this novel pharmacological approach might 'compete' with current pharmacotherapies for obesity and diabetes, while also conceptualizing future CB1-based pharmacological trends that may significantly lower the risk/benefits ratio associated with the use of these drugs.

Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance

Understanding the neural components modulating feeding-related behavior and energy expenditure is crucial to combating obesity and its comorbidities. Neurons within the paraventricular nucleus of the hypothalamus (PVH) are a key component of the satiety response; activation of the PVH decreases feeding and increases energy expenditure, thereby promoting negative energy balance. In contrast, PVH ablation or silencing in both rodents and humans leads to substantial obesity. Recent studies have identified genetically-defined PVH subpopulations that control discrete aspects of energy balance (e.g. oxytocin (OXT), neuronal nitric oxide synthase 1 (NOS1), melanocortin 4-receptor (MC4R), prodynorphin (PDYN)). We previously demonstrated that non-OXT NOS1PVH neurons contribute to PVH-mediated feeding suppression. Here, we identify and characterize a non-OXT, non-NOS1 subpopulation of PVH and peri-PVH neurons expressing insulin-receptor substrate 4 (IRS4PVH) involved in energy balance control. Using Cre-dependent viral tools to activate, trace and silence these neurons, we highlight the sufficiency and necessity of IRS4PVH neurons in normal feeding and energy expenditure regulation. Furthermore, we demonstrate that IRS4PVH neurons lie within a complex hypothalamic circuitry that engages distinct hindbrain regions and is innervated by discrete upstream hypothalamic sites. Overall, we reveal a requisite role for IRS4PVH neurons in PVH-mediated energy balance which raises the possibility of developing novel approaches targeting IRS4PVH neurons for anti-obesity therapies.

Human Pluripotent Stem Cells: A Relevant Model to Identify Pathways Governing Thermogenic Adipocyte Generation.

Brown and brown-like adipocytes (BAs) are promising cell targets to counteract obesity thanks to their potential to drain and oxidize circulating glucose and triglycerides. However, the scarcity of BAs in human adults is a major limitation for energy expenditure based therapies. Enhanced characterization of BA progenitor cells (BAPs) and identification of critical pathways regulating their generation and differentiation into mature BAs would be an effective way to increase the BA mass. The identification of molecular mechanisms involved in the generation of thermogenic adipocytes is progressing substantially in mice. Much less is known in humans, thus highlighting the need for an in vitro model of human adipocyte development. Pluripotent stem cells (PSCs), i.e., embryonic stem cells and induced pluripotent stem cells, help gain insight into the different phases in the development of multiple cell types. We will discuss the capacity of human PSCs to differentiate into BAs in this review. Several groups, including ours, have reported low spontaneous adipocyte generation from PSCs. However, factors governing the differentiation of induced pluripotent stem cell-derived BA progenitors cells were recently identified, and the TGFβ signaling pathway has a pivotal role. The development of new relevant methods, such as the differentiation of hPSC-BAPs into 3D adipospheres to better mimick the lobular structure of human adipose tissue, will also be discussed. Differentiation of human PSCs into thermogenic adipocytes at high frequency provides an opportunity to characterize new targets for anti-obesity therapy.

GDF15 Induces Anorexia through Nausea and Emesis

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and hasbecome a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry.

Yarrow Supercritical Extract Ameliorates the Metabolic Stress in a Model of Obesity Induced by High-Fat Diet.

Nowadays, obesity and its associated metabolic disorders, including diabetes, metabolic syndrome, cardiovascular disease, or cancer, continue to be a health epidemic in westernized societies, and there is an increased necessity to explore anti-obesity therapies including pharmaceutical and nutraceutical compounds. Considerable attention has been placed on the identification of bioactive compounds from natural sources to manage the metabolic stress associated with obesity. In a previous work, we have demonstrated that a CO2 supercritical fluid extract from yarrow (Yarrow SFE), downregulates the expression of the lipogenic master regulator SREBF1 and its downstream molecular targets FASN and SCD in a tumoral context. Since obesity and diabetes are strongly considered high-risk factors for cancer development, herein, we aimed to investigate the potential therapeutic role of Yarrow SFE in the metabolic stress induced after a high-fat diet in mice. For this purpose, 32 C57BL/6 mice were distributed in four groups according to their diets: standard diet (SD); SD supplemented with Yarrow SFE (SD + Yarrow); high-fat diet (HFD); and HFD supplemented with Yarrow SFE (HFD + Yarrow). Fasting glycemia, insulin levels, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile, gene expression, and lipid content of liver and adipose tissues were analyzed after three months of treatment. Results indicate improved fasting glucose levels in plasma, enhanced insulin sensitivity, and diminished hypercholesterolemia in the HFD + Yarrow group compared to the HFD group. Mechanistically, Yarrow SFE protects liver from steatosis after the HFD challenge by augmenting the adipose tissue buffering capacity of the circulating plasma glucose.

The Efficacy of Gynostemma pentaphyllum Extract in Anti-obesity Therapy

The Efficacy of Gynostemma pentaphyllum Extract in Anti-obesity Therapy

Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti-obesity therapies.

GLP-1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer-term administration at the highest dose approved for obesity (liraglutide 3.0 mg). A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo-controlled, double-blind, cross-over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center. While using liraglutide, patients lost more weight (placebo-subtracted -2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons). In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter-regulatory increase in reward-related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.

1999-P: Cysteine-Rich Protein 2 (CRIP2) Is a Novel Transcriptional Regulator of Uncoupling Protein 1

Since traditional weight loss strategies have been unsuccessful at slowing the increasing rate of obesity, alternative strategies are in high demand. Brown adipose tissue (BAT) is a thermogenic tissue that efficiently expends energy. Thermogenesis in BAT occurs through the action of uncoupling protein 1 (UCP1). Identifying novel transcriptional regulators of UCP1 may lead to potential targets to increase BAT activity since its expression is under tight transcriptional control. Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) is a modified CRISPR/Cas9 methodology that identifies novel transcriptional regulators. EnChIP uses dCas9 (lacks endonuclease activity) and guide RNAs (gRNAs) targeting a specific promoter region. The DNA-bound dCas9 can be immunoprecipitated, and the associated promoter region/transcriptional machinery can be sent for proteomic analysis to identify novel transcriptional regulators. Following β-adrenergic stimulation, which activates UCP1 gene transcription in brown adipocytes, we performed enChIP by using five gRNAs targeting the UCP1 promoter. EnChIP analysis of the UCP1 promoter revealed cysteine-rich protein 2 (CRIP2) as a putative transcriptional regulator of UCP1, which was validated by ChIP-PCR. We demonstrated that knocking down CRIP2 in brown adipocytes significantly decreased β-adrenergic-induced UCP1 expression and heat production. Mechanistically, we demonstrated that following β-adrenergic stimulation, CRIP2 was phosphorylated and translocated from the cytosol to the nucleus, where it interacted with peroxisomal proliferator-activated receptor gamma (PPARγ). Taken together, using the unbiased CRISPR-based enChIP approach, we identify CRIP2 as a novel transcriptional regulator that modulates UCP1 expression in response to β-adrenergic stimulation. These findings pave the foundation for developing new anti-obesity and antidiabetes therapies. Disclosure J. Darcy: None. C. Wang: None. M. Lundh: Employee; Self; Gubra. F. Shamsi: None. M. Lynes: None. T. d'Aprigny: None. B. Emanuelli: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd. Funding National Institutes of Health (R01DK077097, R01DK102898, T32DK007260)