Obesity-associated Conditions Research Articles

Association of Birth by Cesarean Delivery With Obesity and Type 2 Diabetes Among Adult Women

Cesarean delivery is associated with an increased risk of childhood obesity in offspring. However, whether this increased risk also includes obesity-associated conditions remains unclear. To evaluate the association of birth by cesarean delivery with offspring's risks of obesity and type 2 diabetes in adulthood. This prospective cohort study compared the incidence of obesity and type 2 diabetes between birth by cesarean delivery and vaginal delivery among 33 226 women participating in the Nurses' Health Study II who were born between 1946 and 1964, with follow-up through the end of the 2013-2015 follow-up cycle. Participants' mothers provided information on mode of delivery and pregnancy characteristics. Participants provided information every 2 years on weight and diagnosis of type 2 diabetes. Relative risks of obesity and type 2 diabetes were estimated using log-binomial and proportional hazards regression accounting for maternal body mass index and other confounding factors. Statistical analysis was performed from June 2017 to December 2019. Birth by cesarean delivery compared with birth by vaginal delivery. Risk of obesity and incidence of type 2 diabetes. At baseline, the participants' mean (SD) age was 33.8 (4.6) years (range, 24.0-44.0 years). A total of 1089 of the 33 226 participants (3.3%) were born by cesarean delivery. After 1 913 978 person-years of follow-up, 12 156 (36.6%) women were obese and 2014 (6.1%) had received a diagnosis of type 2 diabetes. Women born by cesarean delivery were more likely to be classified as obese and to have received a diagnosis of type 2 diabetes during follow-up. The multivariable-adjusted relative risk of obesity among women born by cesarean vs vaginal delivery was 1.11 (95% CI, 1.03-1.19). The multivariable-adjusted hazard ratio for type 2 diabetes among women born by cesarean vs vaginal delivery was 1.46 (95% CI, 1.18-1.81); this association remained significant after additional adjustment for participant's own body mass index (relative risk, 1.34 [95% CI, 1.08-1.67]). These associations persisted when analyses were restricted to women at low risk of cesarean delivery based on maternal characteristics. This study suggests that women born by cesarean delivery may have a higher risk than women born by vaginal delivery of being obese and developing type 2 diabetes during adult life.

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice

The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for Cyp2c29 and 3a11) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels.

The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype.

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift toward a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

Adhesion G-protein coupled receptor 56 is required for 3T3-L1 adipogenesis.

Obesity-associated conditions represent major global health and financial burdens and understanding processes regulating adipogenesis could lead to novel intervention strategies. This study shows that adhesion G-protein coupled receptor 56 (GPR56) gene transcripts are reduced in abdominal visceral white adipose tissue derived from obese Zucker rats versus lean controls. Immunostaining in 3T3-L1 preadipocytes reveals both mitotic cell restricted surface and low level general expression patterns of Gpr56. Gpr56 transcripts are differentially expressed in 3T3-L1 cells during adipogenesis. Transient knockdown (KD) of Gpr56 in 3T3-L1 cells dramatically inhibits differentiation through reducing the accumulation of both neutral cellular lipids (56%) and production of established adipogenesis Pparγ 2 (60-80%), C/ebpα (40-78%) mediator, and Ap2 (56-80%) marker proteins. Furthermore, genome editing of Gpr56 in 3T3-L1 cells created CW2.2.4 and RM4.2.5.5 clones (Gpr56 -/- cells) with compound heterozygous deletion frameshift mutations which abolish adipogenesis. Genome edited cells have sustained levels of the adipogenesis inhibitor β-catenin, reduced proliferation, reduced adhesion, altered profiles, and or abundance of extracellular matrix component gene transcripts for fibronectin, types I, III, and IV collagens and loss of actin stress fibers. β-catenin KD alone is insufficient to restore adipogenesis in Gpr56 -/- cells. Together these data show that Gpr56 is required for adipogenesis in 3T3-L1 cells. This report is the first demonstration that Gpr56 participates in regulation of the adipogenesis developmental program. Modulation of the levels of this protein and/or its biological activity may represent a novel target for development of therapeutic agents for the treatment of obesity.

SUN-104 The Anti-Rheumatic Drug Auranofin Improves The Metabolic Phenotype Of Obesity

Obesity is associated with chronic low-grade inflammation, reflecting significant alterations in the composition of immune cell populations that reside in white adipose tissue (WAT). The ensuing pro-inflammatory environment likely impinges on the metabolic functions of adipocytes and may partially explain the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). We recently demonstrated ectopic expression of the microRNA miR-30a in the subcutaneous fat pad of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. We subsequently pursued the notion that pharmacological inhibitors of inflammation that exhibit a gene expression profile similar to ectopic miR-30a expression in WAT should represent new drugs for insulin resistance and T2DM. To this end, we used the Broad Connectivity Map to analyze a library of small molecules that induce mRNA profiles similar to that of exogenous miR-30a expression in WAT. Through this process, we nominated the rheumatoid arthritis compound auranofin. Treatment of obese mice with auranofin elevated energy expenditure producing weight loss and improvements in insulin sensitivity. Auranofin treatment also normalized other obesity-associated conditions, including hepatic steatosis and serum levels of leptin. Auranofin likely exerts this function by modulating an integrated gene program to oppose low-grade inflammation in WAT. These studies reveal important metabolic properties of anti-inflammatory treatments that may be purposed as therapies for insulin resistance and T2DM.

Cholinergic Control of Inflammation, Metabolic Dysfunction, and Cognitive Impairment in Obesity-Associated Disorders: Mechanisms and Novel Therapeutic Opportunities.

Obesity and obesity-associated disorders have become world-wide epidemics, substantially increasing the risk of debilitating morbidity and mortality. A characteristic feature of these disorders, which include the metabolic syndrome (MetS) and type 2 diabetes, is chronic low-grade inflammation stemming from metabolic and immune dysregulation. Inflammation in the CNS (neuroinflammation) and cognitive impairment have also been associated with obesity-driven disorders. The nervous system has a documented role in the regulation of metabolic homeostasis and immune function, and recent studies have indicated the important role of vagus nerve and brain cholinergic signaling in this context. In this review, we outline relevant aspects of this regulation with a specific focus on obesity-associated conditions. We outline accumulating preclinical evidence for the therapeutic efficacy of cholinergic stimulation in alleviating obesity-associated inflammation, neuroinflammation, and metabolic derangements. Recently demonstrated beneficial effects of galantamine, a centrally acting cholinergic drug and cognitive enhancer, in patients with MetS are also summarized. These studies provide a rationale for further therapeutic developments using pharmacological and bioelectronic cholinergic modulation for clinical benefit in obesity-associated disorders.

Impacts on Hepatic Ontogenic Expression of Drug‐metabolizing Enzymes by High‐fat Diet‐induced Obesity in Mice

The prevalence of obesity‐associated conditions increases up to 30% of general populations globally. A few studies have shown that obesity may lead to altered drug metabolism. Although changed expression of drug‐metabolizing enzymes (DMEs) is reported, the impacts on DMEs due to different obese levels (overweight, obese, and morbidly obese) have not been elucidated. Especially, limited information is available on how obesity alters the expression of DMEs in younger ages. The aim of this study is to investigate impacts of high‐fat diet‐induced obesity (DIO) on the hepatic expression of DMEs in adult and the ontogenic expression in offspring with a focus on cytochrome P450s (CYPs) in a mouse model. The expression of CYPs, as well as constitutive androstane receptor (CAR), pregnane X‐receptor (PXR), hepatocyte nuclear factor (HNF4α), and peroxisome proliferator‐activated receptor α (PPARα) was examined. Adult mice consumed 60 kcal% fat diet (HFD) for 8 or 18 weeks showed a more rapid increase of body weight than 10 kcal% fat diet (LFD) control group. The body weight gain of males was >1.5 fold greater than females in HFD groups. Consistent with the weight gain, fat accumulation was found in the livers of HFD groups. Elevated expression of most selected DMEs and transcription factors was observed in HFD groups, expect for CYP3A16 in 8‐week HFD groups, and CYP1A2 and HNF4α in 18‐week HFD groups. Day 60 offspring derived from HFD‐fed adults showed heavier body weights compared with offspring from LFD‐fed adults. Altered ontogenic expression of CYP1A1, 1A2, 2E1, and UGT1A1 was also observed in HFD offspring. Notably, the changed ontogenic patterns were accompanied by the increased expression of DMEs after day 20 in HFD offspring related to LFD groups. Moreover, similar effects on CAR, PXR, HNF4α, and PPARα were found in HFD offspring, indicating that altered expression pattern of DMEs may due to changed expression of transcription factors. Taken together, our study suggested that obese level of DIO influenced the expression of DMEs in adults and offspring and transcription factors might play roles in the altered expression of DMEs.Support or Funding InformationThis work was supported by grant of NIH R01GM118367 and China Scholarship Council (201707040007).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Changing views in cardiometabolic disease

Metabolism Branched-chain amino acids (BCAAs) are a subset of essential amino acids that are acquired from the diet. In a Perspective, White and Newgard discuss the evidence linking increased circulating BCAAs with obesity-associated conditions, including type 2 diabetes and cardiovascular diseases. The authors discuss how BCAAs can provide biomarkers of cardiometabolic health and also the mechanisms by which BCAAs promote phenotypes of cardiometabolic disease. Science , this issue p. [582][1] [1]: /lookup/doi/10.1126/science.aav0558

Liver Transplantation and Bariatric Surgery: Timing and Outcomes.

Nonalcoholic steatohepatitis (NASH) is projected to become the leading indication for liver transplantation (LT) in the next decade in the United States. Strategies to treat the underlying etiology of NASH, which is almost always obesity, are being pursued. One such strategy is the utilization of bariatric surgery (BS) in the peritransplant period. The use of BS prior to LT could prevent the progression of NASH and abrogate the need for LT. BS at the time of LT or postoperatively has the potential to not only improve obesity-associated conditions such as diabetes, but also the potential to influence the incidence of NASH in the post-LT setting. However, there continues to be no consensus on the use and timing of BS in this patient population. This review aims to discuss the current literature and possible future action.

Elevated GlycA in severe obesity is normalized by bariatric surgery.

Chronic inflammation drives many obesity-associated conditions including atherosclerosis. GlycA, a marker of systemic inflammation with lower intra-individual variability than high sensitivity C-reactive protein, is independently associated with incident cardiovascular events and mortality. Although GlycA is elevated in obesity, correlations with anthropometric measures are modest and the effect of body weight loss on GlycA is untested. Obese (body mass index [BMI] 44.6 ± 6.6 kg/m2 ), non-diabetic women (33.7 ± 8.2 years) undergoing Roux-en-Y gastric bypass (n = 23) or sleeve gastrectomy (n = 31) were prospectively studied at baseline, 6 and 12 months postprocedure. Women with normal BMI (n = 14) served as controls. Bariatric surgery significantly reduced GlycA by 6 months (451 ± 47 μmol/L vs. 383 ± 50 μmol/L; P < 0.001) with further reduction at 12 months (348 ± 41 μmol/L; P < 0.001) and no difference between procedures. At 12 months, despite 41% of surgical subjects maintaining BMI >30 kg/m2 , GlycA levels did not differ between surgical and control subjects (P = 0.13). Increased high density lipoprotein particle size was strongly associated with reduced GlycA (r = -0.49; P < 0.001) and was found to mediate up to 43% of its body weight-loss-associated fall. This is the first study to demonstrate that surgical body weight loss markedly reduces levels of GlycA.

A System-Level Approach to Overweight and Obesity in the Veterans Health Administration.

Healthcare systems are challenged by steady increases in the number of patients who are overweight and obese. Large-scale, evidence-based behavioral approaches for addressing overweight and obesity have been successfully implemented in systems such as the Veterans Health Administration (VHA). These population-based interventions target reduction in risk for obesity-associated conditions through lifestyle change and weight loss, and are associated with modest weight loss. Despite the fact that VHA has increased the overall reach of these behavioral interventions, the number of high-risk overweight and obese patients continues to rise. Recommendations for weight loss medications and bariatric surgery are included in clinical practice guidelines for the management of overweight and obesity, but these interventions are underutilized. During a recent state of the art conference on weight management held by VHA, subject matter experts identified challenges and gaps, as well as potential solutions and overarching policy recommendations, for implementing an integrated system-wide approach for improving population-based weight management.

Adipokines and cardiovascular disease: A comprehensive review.

Adipokines are peptides that signal the functional status of adipose tissue to the brain and other target organs. In adipose tissue dysfunction, adipokine secretion is altered, and this can contribute to a spectrum of obesity-associated conditions including cardiovascular disease. Some adipokines have anti-inflammatory and cardioprotective effects (omentin, apelin, adiponectin). Others are pro-inflammatory with negative impact on cardiovascular function (leptin, visfatin, resistin, adipocyte fatty-acid-binding protein). In the first part, this article reviews the endocrine functions of adipose tissue in general, effects of the distribution and composition of fat tissue, and the roles of cortisol and the renin-angiotensin-aldosterone system in the development of the inflammatory state of addipose tissue. In the second part, the known cardiovascular effects of different adipokines and their clinical potential are discussed in detail.

Abstract P4-03-15: Joint influence by paracrine adipocyte signals and metabolic conditions on breast cancer

Abstract Background: The growing global population of overweight and obese people represents a pressing public health concern. A higher percentage of body fat is linked to an altered metabolic state and an increased risk of chronic metabolic disorders and cancer. Although, the mechanistic explanations for how obesity affects the development, progression and prognosis of cancer is incompletely mapped. Purpose: To investigate the joint influence by adipocytes and metabolic pressure on breast cancer cell expansion. Experimental Design: In vitro differentiated 3T3-L1 adipocytes were exposed to metabolic glucoselow/high and insulinlow/high pressure in order to mimic normal, pre-diabetic, overt diabetic and late diabetic conditions. Adipocyte-conditioned medium was collected and paracrine effects by adipocyte-derived factors on estrogen receptor (ER)-positive (T47D, MCF-7) and ER-negative (MDA-MB-231) breast cancer cell proliferation, molecular adaptations, and cell motility were subsequently analyzed using sulforhodamine B, Western immunoblotting and migration assays. Results: Under normal metabolic conditions, adipocytes stimulated the growth of ER+ (1.1-2.0-fold; P&amp;lt;0.001) and to a greater extent, ER- breast cancer cells (3.1-fold; P&amp;lt;0.001), compared with controls. The joint effects by adipocyte paracrine signals and higher metabolic pressure (overt or late diabetic conditions), further enhanced the proliferative response in both ER+ and ER- cells (1.3-3.5-fold; P&amp;lt;0.01), compared with controls. Furthermore, adipocyte-derived factors induced morphological changes, protrusion extensions and cell migration in the low invasive T47D cells. Additional acquisition of molecular epithelial-mesenchymal transition features were observed in breast cancer cells following co-culturing with adipocyte-derived factors. Conclusion: These study results support the hypothesis that paracrine signals by adipocytes significantly stimulate the proliferation and induction of a more motile phenotype of human breast cancer cells, which is further enhanced under obesity-associated metabolic conditions. Citation Format: Rosendahl AH, Bergqvist M, Lettiero B, Kimbung S, Borgquist S. Joint influence by paracrine adipocyte signals and metabolic conditions on breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-15.

Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity.

Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding. These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance.

Abstract P199: Mas Receptor Deficiency Regulates Obesity-Hypertension and Cardiac Function in Female and Male Mice

Angiotensin-1-7 (Ang-(1-7)) counteracts angiotensin II through effects at Mas receptors (MasR). We demonstrated that sexual dimorphism of obesity-hypertension was associated with dysregulated production of Ang-(1-7). However, the role of MasR in sexual dimorphism of obesity-hypertension has not been examined. MasR deficient mice have also been reported to exhibit deficits in cardiac function. In this study, we hypothesized that deficiency of the MasR would differentially regulate obesity-hypertension in male versus ( vs ) female mice. In addition, we quantified effects of MasR deficiency on cardiac function in obese male mice. Male and female MasR +/+ and -/- mice were fed a low fat (LF, 10%kcal) or high fat (HF, 60% kcal) diet for 16 weeks, and blood pressure was quantified by radiotelemetry. As demonstrated previously, male MasR +/+ mice (24 hr diastolic blood pressure, DBP: LF, 90 ± 3; HF, 96 ± 2 mmHg; P&lt;0.05), but not females (LF, 85 ± 1; HF, 85 ± 2 mmHg), developed hypertension in response to HF feeding. MasR deficiency converted female HF-fed mice to an obesity-hypertension phenotype (DBP: 92 ± 1 mmHg; P&lt;0.05). Surprisingly, male HF-fed MasR -/- mice exhibited reduced DBP compared to HF-fed MasR +/+ males (90 ± 1 vs 96 ± 2 mmHg; P&lt;0.05). To define mechanisms for reductions in DBP of HF-fed male MasR -/- mice, we performed cardiac magnetic resonance (CMR) imaging in both genotypes at 1 month of HF feeding. MasR -/- mice had significantly reduced ejection fraction (EF) compared to MasR +/+ mice at baseline (51.4 ± 2.5 vs 59.3 ± 2.1%; P&lt;0.05) and after one month of HF-feeding (49.8 ± 2.4 vs 52.6 ± 1.9%; P&lt;0.05). Further, CMR imaging demonstrated a thickening of the ventricle wall in MasR -/- mice with 1 month of HF-feeding. MasR +/+ , but not MasR -/- mice, exhibited diet-induced reductions in EF (by 16%; P&lt;0.05) at 1 month of HF feeding, which were reversed by infusion of Ang-(1-7). These results demonstrate that MasR contributes to sexual dimorphism of obesity-hypertension. Ang-(1-7) protects females from obesity-hypertension through the MasR. In contrast, reductions in DBP in obese male mice with MasR deficiency may arise from deficits in cardiac function. These results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.

Metabolism: Inflammation keeps old mice healthy.

Immune cells called regulatory T cells accumulate in fat during ageing. The anti-inflammatory activity of these cells worsens age-associated defects in metabolism, in contrast to its effect in obesity. See Letter p.137 Age-associated insulin resistance (IR) and obesity-associated IR are physiologically distinct forms of adult-onset diabetes. Although macrophage-driven inflammation drives the obesity-associated condition, the mechanisms for age-associated IR are not known. Ronald Evans and colleagues show that fat-resident regulatory T cells (fTreg cells) accumulate in adipose tissue as a function of age, but not obesity. Mice lacking fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. Depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. Although not the main topic of this study, these findings do not support a role for fTreg cells in obesity-associated insulin resistance or in the therapeutic actions of thiazolidinedione or 'glitazone' antidiabetics. This contradicts claims that Treg cells were beneficial and necessary for restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone.

Features of endometrial cancer in patients with 'metabolically healthy' versus 'standard' obesity: the decreasing frequency of metabolically healthy obesity.

Background:As endometrial cancer (EC) prevalence increases with obesity, we aimed to determine whether EC characteristics depend upon obesity type: ‘standard’ (SO) or ‘metabolically healthy obesity’ (MHO).Patients & methods:258 EC patients were included. Data on anthropometry, blood hormones, lipids and glucose, and tumor features were collected.Results:EC clinicopathologic characteristics and clinical stage correlate differently with BMI and obesity type. BMI is related inversely with tumor grade while SO patients are characterized by a more advanced clinical stage than those with MHO. Besides typical insulin resistance signs, EC patients with SO often display a higher serum leptin/adiponectin ratio compared with MHO patients. Historical data suggest a gradual increase in EC patient height and weight, and a decrease in MHO prevalence.Conclusion:It is currently unknown whether the latter observation reflects the evolution of EC, or obesity alongside the current epidemic. Regardless, the reduced MHO prevalence demonstrates the need for more intensive preventive measures aimed at obesity and obesity-associated conditions, including different EC subtypes.

Abstract P114: Mas Receptor Deficiency Increases Diastolic Blood Pressure and Reduces Cardiac Function in Obese Female Mice

Objective: We recently demonstrated that protection of female mice from obesity-induced hypertension was associated with increased plasma concentrations of angiotensin-(1-7) (Ang-(1-7)). Ang-(1-7) is a ligand for Mas receptors (MasR), where the peptide has been reported to promote endothelial release of nitric oxide and reduce blood pressure. In this study, we hypothesized that MasR deficiency will abolish protection of female high fat (HF)-fed mice from the development of obesity-induced hypertension. Methods and Results: Female (8 weeks, C57BL/6) wild type (MasR+/+) and whole body MasR deficient mice (MasR-/-) were fed a HF diet (60% Kcal as fat) for 16 weeks. MasR deficiency had no effect on the development of obesity or glucose intolerance in HF-fed female mice. At week 16 of HF feeding, blood pressure was quantified by radiotelemetry. Deficiency of MasR resulted in a significant decrease in pulse pressures of HF-fed females (24hr average: MasR+/+, 37.7 ± 1.5 mmHg; MasR-/-, 33.1 ± 1.0 mmHg; P&lt;0.05). Diastolic blood pressures (DBP) of HF-fed female MasR-/- mice were modestly elevated during the night cycle compared to controls (DBP night: MasR+/+, 91.5 ± 2.0 mmHg; MasR-/-, 96.6 ± 1.3 mmHg; P=0.06). However, systolic blood pressure, mean arterial pressure and heart rate were not significantly different between genotypes. Assessment of left ventricular function by ultrasound demonstrated significant reductions in stroke volume (MasR+/+, 44.3 ± 1.6 μl; MasR-/-, 36.3 ± 2.1 μl), ejection fraction (MasR+/+, 57.1 ± 1.2; MasR-/-, 50.1 ± 2.7%) and fractional shortening (MasR+/+, 29.7 ± 0.8; MasR-/-, 25.3 ± 1.7%) in HF-fed MasR-/- females compared to controls. Conclusion: These results demonstrate that MasR deficiency promotes elevated diastolic blood pressures and reduced cardiac function in obese female mice, suggesting that the Ang-(1-7)/MasR axis protects females from obesity-hypertension. Moreover, these results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.

Brown adipose tissue and the cold war against obesity.

Obesity is one of the most burdensome health issues of our time. According to a 2012 World Health Organization report, there are more than 1.4 billion overweight adults worldwide, of whom ∼500 million are obese (1). Strikingly, 40 million children under the age of 5 are currently overweight or obese (1). These statistics are especially alarming because of the long list of obesity-associated conditions. These include insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular disease, and several cancers (2). Among the consequences of the obesity epidemic are an expanding population of chronically ill people, escalating health care expenses, and the prediction that, for the first time in human history, the current generation will have a shorter life span than the previous one (3). Accumulation of fat results from a prolonged imbalance between energy intake and energy expenditure. One might think that reducing fat mass in obese individuals could be achieved relatively simply by either decreasing food consumption or increasing energy expenditure, thereby attaining a sustained negative energy balance. Unfortunately, this task is not easy to achieve, in large part because of the combination of sedentary lifestyle and the availability of calorie-dense, inexpensive food. With the exception of bariatric surgery (4), most antiobesity interventions that target energy intake result in moderate, and often temporary, weight loss. Sadly, pharmacological strategies aimed at increasing energy expenditure have not delivered on the promise of efficacy or safety when translated from animal models to humans. For instance, supraphysiologic doses of thyroid …

Formula food-reducing diets:A new evidence-based addition to the weight management tool box.

The changing pattern of obesity-related disease has created a need for a greater range of weight management options for the increasing number of people for whom weight loss and maintenance cannot be addressed by conventional dietary methods.Formula diet weight loss programmes [very low-calorie diets (VLCDs) (400–800 kcal/day) and low-calorie diets (LCDs) (800–1200 kcal/day)] can deliver weight loss at rates of 1–2 kg/week. This rate of weight loss can result in 10–20 kg weight loss in 8–12 weeks. Many health benefits associated with weight reduction seem to require between 10 and 20 kg weight loss. Formula diet programmes can result in weight loss, reduction of liver volume and reduction of visceral fat before bariatric surgery; weight loss before knee joint replacement surgery has also been shown. The benefit of pre-operative weight loss is still under investigation and such practices before bariatric surgery are variable in surgical units across the UK.Weight loss with formula diet in obesity-associated conditions where inflammation is an important component, such as osteoarthritis and psoriasis, has been demonstrated. Maintenance of about 10% of initial bodyweight loss, with symptom improvement in elderly obese people with knee osteoarthritis, has been shown over a period of 4 years. In obese people with psoriasis, weight loss with skin improvement has been maintained for 1 year.Clinical trials are currently underway to examine the merits of an initial weight loss with formula diet in pre-diabetes, in early type 2 diabetes and in insulin-treated type 2 diabetes.Rapid initial weight loss can result in rapid symptom improvement, such as reduced joint pain in osteoarthritis, improved sleep quality in obstructive sleep apnoea, reduced shortness of breath on exertion, reduced peripheral oedema and rapid improvement in metabolic control in diabetes, all changes that are highly motivating and conducive towards compliance.There is also some evidence for improved vitamin D status and maintained bone health in elderly obese people with osteoarthritis but more research is needed.Rapid initial weight loss was feared to be followed by rapid weight regain. However, provided initial weight loss is delivered in parallel with an intense education programme about nutrition, cooking, shopping and lifestyle for long-term maintenance; and where long-term support is provided, subsequent weight maintenance after VLCDs and LCDs has been shown to be possible. A recent literature review identified high-protein diets, obesity drugs and partial use of formula meal replacements as methods which can result in statistically significantly greater weight maintenance after initial weight loss with VLCDs or LCDs.Anxiety about serious adverse side effects seems to be unfounded although users need to be aware of both minor and more serious, though very infrequent, adverse events, such as gallstones and gallbladder disease.