Strategy For Treatment Of Obesity Research Articles

Orchestration of Obesolytic Activity of Microbiome: Metabiotics at Centre Stage.

Metabiotics have emerged as the safer alternatives to probiotics in last decade. Unlike probiotics that are live microbes, metabiotics are the low molecular weight bioactive metabolites produced by the gut microbiota. While offering a similar profile of health benefits as that of probiotics, metabiotics are free from the risks and uncertain responses associated with administration of live bacteria into the body. Metabiotics have demonstrated substantial effectiveness across the ethnicities, age, gender and nutritional habits in a number of metabolic disorders, including obesity. Obesity is attributed to the offsetting of the energy homeostasis of the body due to a number of genetic, endocrinological, and environmental factors leading to obesity. The obesogenic mechanisms are quite complicated as they result from a complex interplay among a number of factors. Owing to a variety of constituents exerting their action through different pathways, metabiotics offer a pragmatic option for treatment as well as prevention of obesity by addressing heterogeneous aspects of its aetiology. In this review, we categorize various components of metabiotics and discuss their cross-talk with host cells at the molecular level. We also discuss the challenges in understanding these interactions and their potential effects on obesity treatment and prevention strategies. Considering the alarming rise in obesity all over the world, metabiotics offer an attractive non-pharmacological approach to spearhead the strategies being designed to combat the challenges posed by the obesity epidemic.

MiR-669a-5p promotes adipogenic differentiation and induces browning in preadipocytes

ABSTRACT Obesity is a major global health issue that contributes to the occurrence of metabolic disorders. Based on this fact, understanding the underlying mechanisms and to uncover promising therapeutic approaches for obesity have attracted intense investigation. Brown adipose tissue (BAT) can help burns excess calories. Therefore, promoting White adipose tissue (WAT) browning and BAT activation is an attractive strategy for obesity treatment. MicroRNAs (miRNAs) are small, non-coding RNAs, which are involved in regulation of adipogenic processes and metabolic functions. Evidence is accumulating that miRNAs are important regulators for both brown adipocyte differentiation and white adipocyte browning. Here we report that the expression of miR-669a-5p increases during the adipogenic differentiation of 3T3-L1 and C3H10T1/2 adipocytes. miR-669a-5p supplementation promotes adipogenic differentiation and causes browning of 3T3-L1 and C3H10T1/2 cells. Moreover, the expression of miR-669a-5p is upregulated in iWAT of mice exposed to cold. These data demonstrate that miR-669a-5p plays a role in regulating adipocyte differentiation and fat browning. Abbreviations: Acadl: long-chain acyl-Coenzyme A dehydrogenase; Acadm: medium-chain acyl-Coenzyme A dehydrogenase; Acadvl: very long-chain acyl-Coenzyme A dehydrogenase, very long chain; Aco2: mitochondrial aconitase 2; BAT: brown adipose tissue; Bmper: BMP-binding endothelial regulator; Cpt1-b:carnitine palmitoyltransferase 1b; Cpt2: carnitine palmitoyltransferase 2; Crat: carnitine acetyltransferase; Cs: citrate synthase; C2MC: Chromosome 2 miRNA cluster; DMEM: Dulbecco’s modified Eagle medium; eWAT: epididymal white adipose tissue; ETC: electron transport chain; FAO: fatty acid oxidation; Fabp4:fatty acid binding protein 4; FBS: fetal bovine serum; Hadha: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; Hadhb: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; HFD: high fat diet; Idh3a: isocitrate dehydrogenase 3 alpha; iWAT: inguinal subcutaneous white adipose tissue; Lpl: lipoprotein lipase; Mdh2: malate dehydrogenase 2; NBCS: NewBorn Calf Serum; mt-Nd1: mitochondrial NADH dehydrogenase 1; Ndufb8:ubiquinone oxidoreductase subunit B8; Nrf1: nuclear respiratory factor 1; Pgc1α: peroxisome proliferative activated receptor gamma coactivator 1 alpha; Pgc1b: peroxisome proliferative activated receptor, gamma, coactivator 1 beta; Pparγ: peroxisome proliferator activated receptor gamma; Prdm16: PR domain containing 16; Rgs4: regulator of G-protein signaling 4; Sdhb: succinate dehydrogenase complex, subunit B; Sdhc: succinate dehydrogenase complex, subunit C; Sdhd: succinate dehydrogenase complex, subunit D; Sh3d21: SH3 domain containing 21; Sfmbt2: Scm-like with four mbt domains 2; TG: triglyceride; TCA: tricarboxylic acid cycle; Tfam: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine, methyl ester; Ucp1: uncoupling protein 1; Uqcrc2: ubiquinol cytochrome c reductase core protein 2; WAT: White adipose tissue

Eating behavior modulates the sensitivity to the central effects of GLP-1 receptor agonist treatment: a secondary analysis of a randomized trial

AimsWe investigated if individuals with higher emotional eating scores are less sensitive to the effects of a GLP-1RA on central responses to food cues. Additionally, we investigated the associations of higher external and restraint eating scores with the sensitivity to the central effects of GLP-1RA. MethodsThis secondary analysis of a randomized crossover study in people with obesity and type 2 diabetes, consisted of two periods of 12-week treatment with liraglutide or insulin glargine. Using functional MRI, we assessed the relation between baseline eating behavior and the effects of the GLP-1RA liraglutide compared with insulin after 10 days and 12 weeks of treatment on brain responses to food cues. ResultsAfter 10 days, higher emotional eating scores were associated with less pronounced GLP-1RA induced reductions in brain responses to food pictures in the amygdala, insula and caudate nucleus. In addition, higher emotional eating scores tended to be associated with less pronounced GLP-1RA increases in brain responses to chocolate milk receipt in the caudate nucleus and insula. After 12 weeks, there were no significant associations between emotional eating scores and liraglutide-induced changes in brain responses to food cues. After 10 days, baseline external eating scores were associated with less pronounced GLP-1RA induced reductions in brain responses to food pictures in the insula, amygdala and orbitofrontal cortex. After 12 weeks, baseline restraint eating scores were associated with more GLP-1RA induced reductions in brain responses to food pictures in the insula and caudate nucleus, and with more GLP-1RA induced reductions in brain responses to the anticipation of chocolate milk in the caudate nucleus. ConclusionsOur findings indicate that individuals with higher baseline emotional eating scores are less sensitive to the central effect of GLP-1RA treatment. Additionally, external eating may also decrease, whereas restraint eating may increase the sensitivity to the treatment effects of GLP-1RAs. These insights may help to optimize treatment strategies for obesity and to select patient groups with better efficacy of GLP-1RA treatment.

Inhibition of high-fat diet–induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms

Obesity is a risk factor for insulin resistance, type 2 diabetes, and cardiovascular diseases. Reticulon-4 (Nogo) is an endoplasmic reticulum–resident protein with unclear functions in obesity. Herein, we investigated the effect of Nogo on obesity and associated metabolic disorders. Human serum samples were collected to explore the relationship between circulating Nogo-B and body mass index value. Nogo-deficient and WT littermate control mice were fed normal chow or high-fat diet (HFD) for 14 weeks, and HFD-induced obese C57BL/6J mice were injected scrambled or Nogo siRNA for 2 weeks. We found that in human and mouse serum, Nogo-B was positively correlated to body mass index/bodyweight and lipid profiles. Reduced Nogo (by genetic deletion or siRNA transfection) protected mice against HFD-induced obesity and related metabolic disorders. We demonstrate that Nogo deficiency reversed HFD-induced whitening of brown adipose tissue, thereby increasing thermogenesis. It also ameliorated lipid accumulation in tissues by activating the adiponectin–adiponectin receptor 1–AMP-activated kinase α signaling axis. Finally, Nogo deficiency potently reduced HFD-induced serum proinflammatory cytokines and infiltration of macrophages into metabolic organs, which is related to enhanced NF-κB p65 degradation via the lysosome pathway. Collectively, our study suggests that reduced levels of Nogo protect mice against HFD-induced obesity by increasing thermogenesis and energy metabolism while inhibiting NF-κB-mediated inflammation. Our results indicate that inhibition of Nogo may be a potential strategy for obesity treatment.

Dietary Betaine Attenuates Obesity: Involvement of Hepatic MicroRNAs

Obesity affects more than one people in three and reduces life expectancy by 5–20 years globally. Dietary intervention is a preferred strategy for prevention and treatment of obesity. Betaine is a derivative of glycine widely distributed in food, and it functions as a methyl donor and osmolyte. Recent studies revealed betaine as a metabolism modulator, but the underlying mechanisms are largely unknown. In this study, high energy diet-induced obesity mice were administrated with betaine at 120 mg/kg bodyweight daily by gavage for 4 weeks. By histology, biochemistry and hormones analysis, dietary betaine was revealed to attenuate obesity by normalizing glucose and lipid metabolism significantly. Subsequently, the hepatic microRNA expression was determined by real-time PCR. It was found that betaine treatment reversed the elevated miR-27a, miR-27b, miR-34a, miR-200b and miR-223 in obese mice. These data confirmed the anti-obesity effect of dietary betaine and provided a novel perspective for understanding its underlying mechanisms.

Withaferin A Promotes White Adipose Browning and Prevents Obesity Through Sympathetic Nerve-Activated Prdm16-FATP1 Axis.

The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA and restored the weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis, and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.

Striking the Balance: GLP-1/Glucagon Co-Agonism as a Treatment Strategy for Obesity.

Obesity and Type 2 diabetes represent global health challenges, and there is an unmet need for long-lasting and effective pharmacotherapies. Although long-acting glucagon-like peptide-1 (GLP-1) analogues are now in routine use for diabetes and are now being utilised for obesity per se, the need for ever better treatments has driven the development of co-agonists, with the theoretical advantages of improved efficacy by targeting multiple pathways and reduced adverse effects. In this review, we highlight the past and present progress in our understanding and development of treatments based on GLP-1/glucagon co-agonism. We also reflect on the divergent effects of varying the GLP-1:glucagon activity and ratio in the context of pre-clinical and human clinical trial findings. In particular, the multiple metabolic actions of glucagon highlight the importance of understanding the contributions of individual hormone action to inform the safe, effective and tailored use of GLP-1/glucagon co-agonists to target weight loss and metabolic disease in the future.

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin.

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

The Role of Gut Microbiota and Its Produced Metabolites in Obesity, Dyslipidemia, Adipocyte Dysfunction, and Its Interventions.

Obesity is becoming an increasing problem worldwide and is often, but not invariably, associated with dyslipidemia. The gut microbiota is increasingly linked to cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes mellitus. However, relatively little focus has been attributed to the role of gut-microbiota-derived metabolites in the development of dyslipidemia and alterations in lipid metabolism. In this review, we discuss current data involved in these processes and point out the therapeutic potentials. We cover the ability of gut microbiota metabolites to alter lipoprotein lipase action, VLDL secretion, and plasma triglyceride levels, and its effects on reverse cholesterol transport, adipocyte dysfunction, and adipose tissue inflammation. Finally, the current intervention strategies for treatment of obesity and dyslipidemia is addressed with emphasis on the role of gut microbiota metabolites and its ability to predict treatment efficacies.

Taurine supplementation in conjunction with exercise modulated cytokines and improved subcutaneous white adipose tissue plasticity in obese women.

Interventions that can modulate subcutaneous white adipose tissue (scWAT) function, such as exercise training and nutritional components, like taurine, modulate the inflammatory process, therefore, may represent strategies for obesity treatment. We investigated the effects of taurine supplementation in conjunction with exercise on inflammatory and oxidative stress markers in plasma and scWAT of obese women. Sixteen obese women were randomized into two groups: Taurine supplementation group (Tau, n = 8) and Taurine supplementation + exercise group (Tau + Exe, n = 8). The intervention was composed of daily taurine supplementation (3g) and exercise training for 8 weeks. Anthropometry, body fat composition, and markers of inflammatory and oxidative stress were determined in plasma and scWAT biopsy samples before and after the intervention. We found that, although taurine supplementation increased taurine plasma levels, no changes were observed for the anthropometric characteristics. However, Tau alone decreased interleukin-6 (IL-6), and in conjunction with exercise (Tau + Exe), increased anti-inflammatory interleukins (IL-15 and IL10), followed by reduced IL1β gene expression in the scWAT of obese women. Tau and Tau + Exe groups presented reduced adipocyte size and increased connective tissue and multilocular droplets. In conclusion, taurine supplementation in conjunction with exercise modulated levels of inflammatory markers in plasma and scWAT, and improved scWAT plasticity in obese women, promoting protection against obesity-induced inflammation. TRN NCT04279600 retrospectively registered on August 18, 2019.

Inflammation in Metabolic and Cardiovascular Disorders-Role of Oxidative Stress.

Cardiovascular diseases (CVD) constitute the main cause of death worldwide. Both inflammation and oxidative stress have been reported to be involved in the progress of CVD. It is well known that generation of oxidative stress during the course of CVD is involved in tissue damage and inflammation, causing deleterious effects such as hypertension, dysfunctional metabolism, endothelial dysfunction, stroke, and myocardial infarction. Remarkably, natural antioxidant strategies have been increasingly discovered and are subject to current scientific investigations. Here, we addressed the activation of immune cells in the context of ROS production, as well as how their interaction with other cellular players and further (immune) mediators contribute to metabolic and cardiovascular disorders. We also highlight how a dysregulated complement system contributes to immune imbalance and tissue damage in the context of increases oxidative stress. Additionally, modulation of hypothalamic oxidative stress is discussed, which may offer novel treatment strategies for type-2 diabetes and obesity. Together, we provide new perspectives on therapy strategies for CVD caused by oxidative stress, with a focus on oxidative stress.

The mediating role of emotional eating in the relationship between perceived stress and dietary intake quality in Hispanic/Latino adolescents

Obesity rates have steadily increased over the past three decades, and large racial/ethnic disparities in childhood obesity rates—specifically for Hispanic/Latino youth—highlight the major need for identifying and examining key mechanisms of obesogenic behaviors for this at-risk population. This study investigates the relationship between stress and dietary quality in Hispanic/Latino adolescents and seeks to determine the mediating role of emotional eating as a behavioral mechanism. Baseline data from 169 adolescents enrolled in the Imagine HEALTH trial were used to investigate these relationships. Perceived stress and emotional eating were assessed with age-validated questionnaires, and dietary quality was measured via 24-hour recall dietary assessments (later calculated as individual Healthy Eating Index-2015 scores). Nonparametric bootstrapping was used to test the primary hypothesis that emotional eating partially or fully mediates the relationship between perceived stress and dietary quality in this sample, and to test the significance of the mediating effect. Results indicate that emotional eating partially mediates the relationship between perceived stress and dietary quality. The total effect of perceived stress scores on dietary quality scores was −0.24 (p = .006); the direct effect of perceived stress scores on dietary quality scores (controlling for emotional eating scores) was −0.16 (p = .107), and the mediating (indirect) effect of emotional eating was −0.09 (p = .001). The proportion of mediation was 0.36 (36%) (p = .008). This study identifies an important mechanism of obesogenic behavior and can be used to inform future obesity prevention and intervention strategies tailored for the Hispanic/Latino adolescent population.

The Arcuate Nucleus of the Hypothalamus and Metabolic Regulation: An Emerging Role for Renin-Angiotensin Pathways.

Obesity is a chronic state of energy imbalance that represents a major public health problem and greatly increases the risk for developing hypertension, hyperglycemia, and a multitude of related pathologies that encompass the metabolic syndrome. The underlying mechanisms and optimal treatment strategies for obesity, however, are still not fully understood. The control of energy balance involves the actions of circulating hormones on a widely distributed network of brain regions involved in the regulation of food intake and energy expenditure, including the arcuate nucleus of the hypothalamus. While obesity is known to disrupt neurocircuits controlling energy balance, including those in the hypothalamic arcuate nucleus, the pharmacological targeting of these central mechanisms often produces adverse cardiovascular and other off-target effects. This highlights the critical need to identify new anti-obesity drugs that can activate central neurocircuits to induce weight loss without negatively impacting blood pressure control. The renin–angiotensin system may provide this ideal target, as recent studies show this hormonal system can engage neurocircuits originating in the arcuate nucleus to improve energy balance without elevating blood pressure in animal models. This review will summarize the current knowledge of renin–angiotensin system actions within the arcuate nucleus for control of energy balance, with a focus on emerging roles for angiotensin II, prorenin, and angiotensin-(1–7) pathways.

Current Treatments for Obesity: An Update

Obesity is one of the biggest health problems in the world. It is not only a key developer of various dangerous diseases like coronary heart disease, type 2 diabetes mellitus, and sleep apnoea, but is also associated with high mortality and morbidity rate. In recent years, doctors have shifted their attention towards the prevention and treatment of obesity rather than letting the person move towards different diseases and then curing those multiple disorders. One of those strategies for obesity treatment includes bariatric surgery. This review paper encapsulates multiple other strategies like dietary, pharmaceutical, and surgical options available at present for the treatment of obesity. Keywords: Obesity, weight, diabetes, heart disease.

Obesity and dietary fat influence dopamine neurotransmission: exploring the convergence of metabolic state, physiological stress, and inflammation on dopaminergic control of food intake

The aim of this review is to explore how metabolic changes induced by diets high in saturated fat (HFD) affect nucleus accumbens (NAc) dopamine neurotransmission and food intake, and to explore how stress and inflammation influence this process. Recent evidence linked diet-induced obesity and HFD with reduced dopamine release and reuptake. Altered dopamine neurotransmission could disrupt satiety circuits between NAc dopamine terminals and projections to the hypothalamus. The NAc directs learning and motivated behaviours based on homeostatic needs and psychological states. Therefore, impaired dopaminergic responses to palatable food could contribute to weight gain by disrupting responses to food cues or stress, which impacts type and quantity of food consumed. Specifically, saturated fat promotes neuronal resistance to anorectic hormones and activation of immune cells that release proinflammatory cytokines. Insulin has been shown to regulate dopamine neurotransmission by enhancing satiety, but less is known about effects of diet-induced stress. Therefore, changes to dopamine signalling due to HFD warrant further examination to characterise crosstalk of cytokines with endocrine and neurotransmitter signals. A HFD promotes a proinflammatory environment that may disrupt neuronal endocrine function and dopamine signalling that could be exacerbated by the hypothalamic-pituitary-adrenal and κ-opioid receptor stress systems. Together, these adaptive changes may dysregulate eating by changing NAc dopamine during hedonic versus homeostatic food intake. This could drive palatable food cravings during energy restriction and hinder weight loss. Understanding links between HFD and dopamine neurotransmission will inform treatment strategies for diet-induced obesity and identify molecular candidates for targeted therapeutics.

Physical Activity and Social Network Use of Adolescents in Overweight and Obesity Treatment.

Tackling obesity among adolescents requires the optimization of existing obesity treatment strategies. For this purpose, social and personal circumstances, individual needs and behavior of therapy participants need to be analyzed to tailor aims, content and methods of therapy interventions to the target groups. A total of 432 obesity therapy participants between 11 and 17 years completed a written survey in a national multi-center study conducted in 2015. The data collection on behavior, in terms of physical activity, media use and sociodemographic variables, was based on questionnaires from the KiGGS, HBSC and JIM studies. The results show that participants were found to be physically active together with friends (75.5%), alone (41.4%) and in sports clubs (34.9%). Girls (OR 1.55) were less likely to participate in sports clubs. Social networks, especially YouTube, WhatsApp, Instagram and Facebook, were widely used. However, differences emerged among sociodemographic groups (e.g., boys vs. girls) regarding the use of social network features. A third of participants reported that smartphone apps regularly encouraged them to exercise. The findings imply that obesity therapy approaches need to be adapted and more differentiated according to the specific needs of the target groups.

Metabolic profiling and biological activities of the aerial parts of Micromeria imbricata Forssk. growing in Saudi Arabia.

The hydroalcoholic extract (MIT) of Micromeria imbricata (Forssk.) growing in Saudi Arabia in addition to the chloroform (MIC) and n-butanol (MIB) fractions were investigated for the first time using UPLC-ESI-MS/MS. The analysis revealed the tentative identification of fifty-eight compounds including three organic acids, twenty-five phenolic compounds, three coumarins, two anthocyanins, twenty-one flavonoids, three terpenes, and one miscellaneous. Moreover, the therapeutic potential of M. imbricata (MIT) and its fractions (MIC and MIB) were determined by in vitro evaluation of their cytotoxic, antioxidant, and anti-obesity characteristics. The MIT extract showed the highest phenolic (125.23 ± 0.87 mg gallic acid equivalent/100 gm extract) and flavonoid (112.24 ± 2.45 mg quercetin equivalent/100 gm extract) contents followed by n-butanol and chloroform fractions. The MIT extract revealed a potent cytotoxic activity against HepG-2 (Hepatocellular carcinoma) and MCF-7 (Breast carcinoma) with IC50 28.5 ± 2.0 and 35.2 ± 1.2 µg/mL, respectively. Additionally, the tested hydroalcoholic extract exhibited a significant DPPH scavenging activity with SC50 28.4 ± 1.2 µg/mL and a remarkable lipase inhibitory activity with IC50 54.2 ± 1.2 µg/mL. In conclusion, the current study presents the first insights into the phytochemical constituents and pharmacological properties of M. imbricata extract and its chloroform and n-butanol fractions. The results revealed that M. imbricata hydroalcoholic extract might be a prolific source of bioactive constituents with potent antioxidant, cytotoxic and anti-obesity potential. It might be a natural alternative therapy and nutritional strategy for obesity treatment.

Chronic High Fat Diet Disrupts Angiotensin‐(1‐7) Mas Receptor Localization in the Arcuate Nucleus of the Hypothalamus

Introduction The control of energy balance involves communication of peripheral hormones with brain regions controlling food intake and energy expenditure such as the arcuate nucleus of the hypothalamus (ARC). Within the ARC, two primary neuronal subpopulations control energy balance: proopiomelanocortin (POMC) neurons, which reduce food intake and increase energy expenditure; and agouti-related protein (AgRP) neurons, which inhibit POMC neurons and conversely increase food intake and suppress energy expenditure. These circuits are typically disrupted by high fat diet (HFD) leading to a chronic state of energy imbalance and obesity. Accumulating evidence suggests that HFD-induced obesity is associated with deficiency of angiotensin (Ang)-(1-7), a protective renin-angiotensin system hormone. Our recent data show that systemically administered Ang-(1-7) induces adipose thermogenesis to enhance energy expenditure and promote weight loss. We propose that effects of Ang-(1-7) on energy balance involve activation of ARC neurocircuits, but this has not been tested. Additionally, the localization and neuronal subpopulations expressing Ang-(1-7) mas receptors (MasR) in the ARC is unknown. In this study, we hypothesized that: Ang-(1-7) activates ARC neurons; MasR are expressed in the ARC and are primarily colocalized with POMC neurons; and the ability of Ang-(1-7) to activate ARC neurons as well as co-localization of MasR with POMC neurons is disrupted following chronic HFD. Methods Male C57Bl/6J mice were fed a 60% HFD or matched control diet ad libitum for 12 weeks. Mice then received subcutaneous injection of Ang-(1-7) [2 mg/kg] to induce neuronal activation in the ARC, as measured by c-fos gene expression (n=4-6/group). In a second cohort of mice, RNAscope in situ hybridization was performed on coronal ARC sections to determine co-localization of MasR mRNA within POMC versus AgRP neurons (n=5/group). Results We found that Ang-(1-7) increases the number of c-fos positive cells in the ARC (39±6 vs. 19±3 saline; p=0.022) in control diet mice. Ang-(1-7)-mediated activation of ARC neurons was attenuated in HFD mice (34±3 vs. 23±4 saline; p=0.185). The rostral-medial-caudal distribution of ARC MasR was similar between control diet and HFD mice, with no difference in percentage of MasR positive neurons between groups (18±1 and 15±5%, respectively; p=0.733). MasR were more highly co-localized to POMC versus AgRP neurons, with HFD tending to reduce these co-localizations (MasR/POMC: 49±10 control vs. 33±5% HFD, p=0.199; MasR/AgRP: 36±11 control vs.16±7% HFD, p=0.209). Conclusions These findings suggest that chronic HFD reduces the ability of Ang-(1-7) to acutely activate neurons in the ARC. Further, HFD disrupts co-localization of MasR with POMC and AgRP neurons in the ARC indicating disconnect in the endogenous neurocircuitry controlling energy balance. Further studies are needed to explore the importance of MasR in these neuronal subpopulations for energy balance, to determine the potential for targeting of Ang-(1-7) as an innovative pharmacological strategy for obesity treatment.

Memory and Executive Function in Adolescent and Young Adult Females with Moderate to Severe Obesity Before and After Weight Loss Surgery.

There is a global increase in the prevalence of severe obesity in females during adolescence, which is a critical period for neurocognitive development. An increasing number of adolescents and young adults are now undergoing weight loss surgery as a treatment strategy for obesity. In addition to metabolic complications, obesity has been linked to neurocognitive comorbidity, and studies exploring cognitive performance in adolescents with severe obesity and the impact of bariatric surgery on cognitive abilities are limited. Verbal memory and executive function were assessed cross-sectionally in 69 females with moderate to severe obesity and 24 females without obesity, 13-24 years old. In an exploratory analysis, cognitive changes were also assessed longitudinally over 12 months in a subset of 35 females with moderate to severe obesity following weight loss surgery (n = 21) or following usual care without surgery (n = 14). In cross-sectional analysis, females with moderate to severe obesity showed lower scores for short-term and long-term recall (verbal memory) and response inhibition and cognitive flexibility (executive function) than the comparison group, when adjusted for age and baseline intelligence. Females with moderate to severe obesity who underwent surgery showed significant weight loss but no improvement in verbal memory and executive function scores over 12 months compared with those who did not have surgery. Females with moderate to severe obesity demonstrate worse performance in tests of verbal memory and executive function than the comparison group without obesity. In addition, exploratory analyses provide no indication that weight loss surgery improves these observed cognitive decrements over a period of 12 months. Further studies are necessary to comprehensively evaluate changes in cognitive function following bariatric surgery.

3）肥満症の統合的な治療戦略―減量（代謝）手術と肥満2型糖尿病―

3）肥満症の統合的な治療戦略―減量（代謝）手術と肥満2型糖尿病―