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1.
Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity-Breast Cancer Links.
Bustamante-Marin, XM, Merlino, JL, Devericks, E, Carson, MS, Hursting, SD, Stewart, DA
Frontiers in endocrinology. 2021;:632284
Abstract
The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.
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2.
Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, double-blind, placebo-controlled, clinical trial.
Neeland, IJ, Marso, SP, Ayers, CR, Lewis, B, Oslica, R, Francis, W, Rodder, S, Pandey, A, Joshi, PH
The lancet. Diabetes & endocrinology. 2021;(9):595-605
Abstract
BACKGROUND Visceral and ectopic fat are key drivers of adverse cardiometabolic outcomes in obesity. We aimed to evaluate the effects of injectable liraglutide 3·0 mg daily on body fat distribution in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk. METHODS In this randomised, double-blind, placebo-controlled, phase 4, single centre trial, we enrolled community-dwelling adults, recruited from the University of Texas Southwestern Medical Center, with BMI of at least 30 kg/m2 or BMI of at least 27 kg/m2 with metabolic syndrome but without diabetes and randomly assigned them, in a 1:1 ratio, to 40 weeks of treatment with once-daily subcutaneous liraglutide 3·0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. The primary endpoint was percentage reduction in visceral adipose tissue (VAT) measured with MRI. All randomly assigned participants with a follow-up imaging assessment were included in efficacy analyses and all participants who received at least one dose of study drug were included in the safety analyses. The trial is registered on ClinicalTrials.gov: NCT03038620. FINDINGS Between July 20, 2017 and Feb 21, 2020 from 235 participants assessed for eligibility, 185 participants were randomly assigned (n=92 liraglutide, n=93 placebo) and 128 (n=73 liraglutide, n=55 placebo) were included in the final analysis (92% female participants, 37% Black participants, 24% Hispanic participants, mean age 50·2 years (SD 9·4), mean BMI 37·7 kg/m2). Mean change in VAT over median 36·2 weeks was -12·49% (SD 9·3%) with liraglutide compared with -1·63% (SD 12·3%) with placebo, estimated treatment difference -10·86% (95% CI -6·97 to -14·75, p<0·0001). Effects seemed consistent across subgroups of age, sex, race-ethnicity, BMI, and baseline prediabetes. The most frequently reported adverse events were gastrointestinal-related (43 [47%] of 92 with liraglutide and 12 [13%] of 93 with placebo) and upper respiratory tract infections (10 [11%] of 92 with liraglutide and 14 [15%] of 93 with placebo). INTERPRETATION In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3·0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes. FUNDING NovoNordisk.
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Total-body PET Imaging: A New Frontier for the Assessment of Metabolic Disease and Obesity.
Chondronikola, M, Sarkar, S
PET clinics. 2021;(1):75-87
Abstract
Obesity and associated metabolic syndrome are a global public health issue. Understanding the pathophysiology of this systemic disease is of critical importance for the development of future therapeutic interventions to improve clinical outcomes. The multiorgan nature of the pathophysiology of obesity presents a unique challenge. Total-body PET imaging, either static or dynamic, provides a vital set of tools to study organ crosstalk. The visualization and quantification of tissue metabolic kinetics with total-body PET in health and disease provides essential information to better understand disease physiology and potentially develop diagnostic and therapeutic modalities.
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Metabolic, Affective and Neurocognitive Characterization of Metabolic Syndrome Patients with and without Food Addiction. Implications for Weight Progression.
Camacho-Barcia, L, Munguía, L, Lucas, I, de la Torre, R, Salas-Salvadó, J, Pintó, X, Corella, D, Granero, R, Jiménez-Murcia, S, González-Monje, I, et al
Nutrients. 2021;(8)
Abstract
According to the food addiction (FA) model, the consumption of certain types of food could be potentially addictive and can lead to changes in intake regulation. We aimed to describe metabolic parameters, dietary characteristics, and affective and neurocognitive vulnerabilities of individuals with and without FA, and to explore its influences on weight loss progression. The sample included 448 adults (55-75 years) with overweight/obesity and metabolic syndrome from the PREDIMED-Plus cognition sub-study. Cognitive and psychopathological assessments, as well as dietary, biochemical, and metabolic measurements, were assessed at baseline. Weight progression was evaluated after a 3-year follow up. The presence of FA was associated with higher depressive symptomatology, neurocognitive decline, low quality of life, high body mass index (BMI), and high waist circumference, but not with metabolic comorbidities. No differences were observed in the dietary characteristics except for the saturated and monounsaturated fatty acids consumption. After three years, the presence of FA at baseline resulted in a significantly higher weight regain. FA is associated with worse psychological and neurocognitive state and higher weight regain in adults with metabolic syndrome. This condition could be an indicator of bad prognosis in the search for a successful weight loss process.
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Implementing the international evidence-based guideline of assessment and management of polycystic ovary syndrome (PCOS): how to achieve weight loss in overweight and obese women with PCOS?
Lie Fong, S, Douma, A, Verhaeghe, J
Journal of gynecology obstetrics and human reproduction. 2021;(6):101894
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Many of these women are overweight or obese. A minor weight loss of 5%-10% can significantly reduce reproductive, metabolic and psychological symptoms of PCOS and is recommended as a first step in the treatment of overweight or obese women with PCOS. Many weight loss programs have been proposed, but optimal methods on how to achieve the recommend weight loss are lacking. The aim of this systematic review was to generate practical tools for health professionals to guide women with PCOS towards a sustainable healthier lifestyle. PRISMA guidelines were used to conduct the systematic review. Eleven randomized controlled trials were found eligible for inclusion. Lifestyle modification strategies consisted of a diet, physical exercise, behavioural coaching or combined interventions. Mean weight loss ranged from +0.5 to -10.6 % of the initial body weight. However, the majority of the studies reported considerable drop-out rates varying between 12% and 47%. The heterogeneity of the described interventions and the high drop-out rates impede extrapolation of these results to daily clinical care. Hence, none of the described interventions seems superior to another in achieving substantial weight loss. In conclusion, the need for obtaining a healthier weight in overweight and obese women with PCOS is now well accepted. However, achieving this goal remains a challenge for both patients and healthcare providers. More research focusing on the multidisciplinary approach of lifestyle modification advice in daily practice is needed.
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The use of anti-obesity medications in people with mental illness as an adjunct to lifestyle interventions - Effectiveness, tolerability and impact on eating behaviours: A 52-week observational study.
Tham, M, Chong, TWH, Jenkins, ZM, Castle, DJ
Obesity research & clinical practice. 2021;(1):49-57
Abstract
OBJECTIVE The increasing prevalence of obesity and metabolic syndrome in people with mental illness (MI) is a global health priority. Anti-obesity medications (AOMs) may help with reducing medication induced hunger and weight gain when lifestyle changes are insufficient. Our aim is to evaluate the effectiveness, tolerability, impact on eating behaviours and psychiatric safety of AOMs in this population. METHODS We conducted an observational study of 244 adults with MI with at least two risk factors for metabolic syndrome attending an obesity management clinic. Participants received standardised diet, exercise and psychological care, in addition to AOMs tailored to each participant's circumstances. Baseline and 12-month assessments encompassing physical, metabolic and psychological parameters were compared. RESULTS Over the course of the study, the average weight loss was 11.79 kg (12.1%), decrease in BMI was 3.90 kg/m2 and reduction in waist circumference was 12.6 cm. Participants with good glycaemic control increased from 28.6% to 80.7%, hypercholesterolaemia reduced from 85.2%-29.9% and hypertension rates reduced from 88.9%-52.0%. Depression, anxiety and stress levels for the sample decreased significantly (all p < .01). Eating behaviours improved (all p < .001) at follow-up. Psychiatric side effects including deterioration of mood (28.2%) and suicidality (30.8%) were primarily experienced by those on topiramate. CONCLUSIONS AOMs can be effective in achieving clinically meaningful weight loss, improved metabolic co-morbidities and eating behaviours in people living with MI, when combined with a comprehensive lifestyle program. The majority of AOMs are well tolerated but topiramate appears more likely to negatively impact mental health.
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7.
Global pandemics interconnected - obesity, impaired metabolic health and COVID-19.
Stefan, N, Birkenfeld, AL, Schulze, MB
Nature reviews. Endocrinology. 2021;(3):135-149
Abstract
Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), obesity and impaired metabolic health also emerged as important determinants of severe coronavirus disease 2019 (COVID-19). Furthermore, novel findings indicate that specifically visceral obesity and characteristics of impaired metabolic health such as hyperglycaemia, hypertension and subclinical inflammation are associated with a high risk of severe COVID-19. In this Review, we highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19. We also summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs. In addition, we discuss data indicating that the COVID-19 pandemic could have serious consequences for the obesity epidemic. As obesity and impaired metabolic health are both accelerators and consequences of severe COVID-19, and might adversely influence the efficacy of COVID-19 vaccines, we propose strategies for the prevention and treatment of obesity and impaired metabolic health on a clinical and population level, particularly while the COVID-19 pandemic is present.
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Effects of macronutrient intake in obesity: a meta-analysis of low-carbohydrate and low-fat diets on markers of the metabolic syndrome.
Willems, AEM, Sura-de Jong, M, van Beek, AP, Nederhof, E, van Dijk, G
Nutrition reviews. 2021;(4):429-444
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Abstract
The metabolic syndrome (MetS) comprises cardiometabolic risk factors frequently found in individuals with obesity. Guidelines to prevent or reverse MetS suggest limiting fat intake, however, lowering carbohydrate intake has gained attention too. The aim for this review was to determine to what extent either weight loss, reduction in caloric intake, or changes in macronutrient intake contribute to improvement in markers of MetS in persons with obesity without cardiometabolic disease. A meta-analysis was performed across a spectrum of studies applying low-carbohydrate (LC) and low-fat (LF) diets. PubMed searches yielded 17 articles describing 12 separate intervention studies assessing changes in MetS markers of persons with obesity assigned to LC (<40% energy from carbohydrates) or LF (<30% energy from fat) diets. Both diets could lead to weight loss and improve markers of MetS. Meta-regression revealed that weight loss most efficaciously reduced fasting glucose levels independent of macronutrient intake at the end of the study. Actual carbohydrate intake and actual fat intake at the end of the study, but not the percent changes in intake of these macronutrients, improved diastolic blood pressure and circulating triglyceride levels, without an effect of weight loss. The homeostatic model assessment of insulin resistance improved with both diets, whereas high-density lipoprotein cholesterol only improved in the LC diet, both irrespective of aforementioned factors. Remarkably, changes in caloric intake did not play a primary role in altering MetS markers. Taken together, these data suggest that, beyond the general effects of the LC and LF diet categories to improve MetS markers, there are also specific roles for weight loss, LC and HF intake, but not reduced caloric intake, that improve markers of MetS irrespective of diet categorization. On the basis of the results from this meta-analysis, guidelines to prevent MetS may need to be re-evaluated.
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Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models.
Depommier, C, Flamand, N, Pelicaen, R, Maiter, D, Thissen, JP, Loumaye, A, Hermans, MP, Everard, A, Delzenne, NM, Di Marzo, V, et al
Cells. 2021;(1)
Abstract
The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity.
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Mechanisms of action of duodenal mucosal resurfacing in insulin resistant women with polycystic ovary syndrome.
Kaur, V, Dimitriadis, GK, Pérez-Pevida, B, Bansi, DS, Jayasena, C, Bate, D, Houghton, R, Fielding, BA, Balfoussia, D, Webber, L, et al
Metabolism: clinical and experimental. 2021;:154908
Abstract
BACKGROUND Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans. METHODS Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention. RESULTS A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion. CONCLUSIONS These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa.