Physical Activity and Excess Body Weight and Adiposity for Adults. American College of Sports Medicine Consensus Statement.

ABSTRACT: Excessive body weight and adiposity contribute to many adverse health concerns. The American College of Sports Medicine (ACSM) recognizes that the condition of excess body weight and adiposity is complex, with numerous factors warranting consideration. The ACSM published a position stand on this topic in 2001 with an update in 2009, and a consensus paper on the role of physical activity in the prevention of weight gain in 2019. This current consensus paper serves as an additional update to those prior ACSM position and consensus papers. The ACSM supports the inclusion of physical activity in medical treatments (pharmacotherapy, metabolic and bariatric surgery) of excess weight and adiposity, as deemed to be medically appropriate, and provides perspectives on physical activity within these therapies. For weight loss and prevention of weight gain, the effects may be most prevalent when physical activity is progressed in an appropriate manner to at least 150 min·wk-1 of moderate-intensity physical activity, and these benefits occur in a dose-response manner. High-intensity interval training does not appear to be superior to moderate-to-vigorous physical activity for body weight regulation, and light-intensity physical activity may also be an alternative approach provided it is of sufficient energy expenditure. Evidence does not support that any one single mode of physical activity is superior to other modes for the prevention of weight gain or weight loss, and to elicit holistic health benefits beyond the effects on body weight and adiposity, multimodal physical activity should be recommended. The interaction between energy expenditure and energy intake is complex, and the effects of exercise on the control of appetite are variable between individuals. Physical activity interventions should be inclusive and tailored for sex, self-identified gender, race, ethnicity, socioeconomic status, age, and developmental level. Intervention approaches can also include different forms, channels, and methods to support physical activity.

Medical Weight Management Considerations in Plastic Surgery.

BRIEF SUMMARY: Obesity is one of the largest public health concerns in the US and has reached an epidemic scope over the last few decades. Plastic surgery in patients with obesity has been linked to higher complications both before and after weight loss. This article aims to discuss the evolution and current landscape of anti-obesity medications (AOMs) as they apply to the plastic surgeon. Although bariatric surgery has been effective in long-term treatment, new pharmacologic advances in GLP-1 agonists such as semaglutide have demonstrated promising effectiveness. These medications pose several unique challenges, particularly with regards to perioperative management and risk of weight regain after discontinuation. An understanding of these new pharmacologic agents is crucial for plastic surgeons as we treat those affected by obesity.

American Society for Gastrointestinal Endoscopy-European Society of Gastrointestinal Endoscopy guideline on primary endoscopic bariatric and metabolic therapies for adults with obesity.

This joint ASGE-ESGE guideline provides an evidence-based summary and recommendations regarding the role of endoscopic bariatric and metabolic therapies (EBMTs) in the management of obesity. The document was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. It evaluates the efficacy and safety of EBMT devices and procedures that currently have CE mark or FDA-clearance/approval, or that had been approved within five years of document development. The guideline suggests the use of EBMTs plus lifestyle modification in patients with a BMI of ≥30 kg/m2, or with a BMI of 27.0-29.9 kg/m2 with at least 1 obesity-related comorbidity. Furthermore, it suggests the utilization of intragastric balloons and devices for endoscopic gastric remodeling (EGR) in conjunction with lifestyle modification for this patient population.

American Society for Gastrointestinal Endoscopy-European Society of Gastrointestinal Endoscopy guideline on primary endoscopic bariatric and metabolic therapies for adults with obesity.

This joint ASGE-ESGE guideline provides an evidence-based summary and recommendations regarding the role of endoscopic bariatric and metabolic therapies (EBMTs) in the management of obesity. The document was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. It evaluates the efficacy and safety of EBMT devices and procedures that currently have CE mark or FDA-clearance/approval, or that had been approved within five years of document development. The guideline suggests the use of EBMTs plus lifestyle modification in patients with a BMI of ≥ 30 kg/m2, or with a BMI of 27.0-29.9 kg/m2 with at least 1 obesity-related comorbidity. Furthermore, it suggests the utilization of intragastric balloons and devices for endoscopic gastric remodeling (EGR) in conjunction with lifestyle modification for this patient population.

Glucose-dependent insulinotropic polypeptide monoclonal antibodies prevent and treat obesity in wild-type and hyperphagic mice.

OBJECTIVE: This study aimed to investigate whether a glucose-dependent insulinotropic polypeptide (GIP) monoclonal antibody (mAb) will promote weight loss in wild-type mice and to determine effects of this mAb in preventing weight gain in ob/ob mice. METHODS: Phosphate-buffered saline (PBS) or GIP mAb was injected intraperitoneally to wild-type mice fed a 60% high-fat diet (HFD). After 12 weeks, mice that received PBS were divided into two groups and were fed a 37% HFD for 5 weeks; one group received PBS, and one group received GIP mAb. In a separate study, PBS or GIP mAb was injected intraperitoneally to ob/ob mice fed normal mouse chow for 8 weeks. RESULTS: PBS-treated mice gained significantly more than those treated with GIP mAb, with no difference in food consumption detected. Obese mice fed a 37% HFD and PBS continued to gain weight (+2.1% ± 0.9%), whereas mice administered GIP mAb lost 4.1% ± 1.4% body weight (p < 0.01). Leptin-deficient mice consumed similar amounts of chow, and, after 8 weeks, the PBS- and GIP mAb-treated mice gained 250.4% ± 9.1% and 192.4% ± 7.3%, respectively (p < 0.01). CONCLUSIONS: These studies support the hypothesis that a reduction in GIP signaling appears to affect body weight without suppressing food intake and might provide a novel, useful method for the treatment and prevention of obesity.

Preoperative Depression Status and 5 Year Metabolic and Bariatric Surgery Outcomes in the PCORnet Bariatric Study Cohort.

OBJECTIVE: To examine whether depression status before metabolic and bariatric surgery (MBS) influenced 5-year weight loss, diabetes, and safety/utilization outcomes in the PCORnet Bariatric Study. SUMMARY OF BACKGROUND DATA: Research on the impact of depression on MBS outcomes is inconsistent with few large, long-term studies. METHODS: Data were extracted from 23 health systems on 36,871 patients who underwent sleeve gastrectomy (SG; n=16,158) or gastric bypass (RYGB; n=20,713) from 2005-2015. Patients with and without a depression diagnosis in the year before MBS were evaluated for % total weight loss (%TWL), diabetes outcomes, and postsurgical safety/utilization (reoperations, revisions, endoscopy, hospitalizations, mortality) at 1, 3, and 5 years after MBS. RESULTS: 27.1% of SG and 33.0% of RYGB patients had preoperative depression, and they had more medical and psychiatric comorbidities than those without depression. At 5 years of follow-up, those with depression, versus those without depression, had slightly less %TWL after RYGB, but not after SG (between group difference = 0.42%TWL, P = 0.04). However, patients with depression had slightly larger HbA1c improvements after RYGB but not after SG (between group difference = - 0.19, P = 0.04). Baseline depression did not moderate diabetes remission or relapse, reoperations, revision, or mortality across operations; however, baseline depression did moderate the risk of endoscopy and repeat hospitalization across RYGB versus SG. CONCLUSIONS: Patients with depression undergoing RYGB and SG had similar weight loss, diabetes, and safety/utilization outcomes to those without depression. The effects of depression were clinically small compared to the choice of operation.

Approaches to addressing the rise in obesity levels.

Levels of obesity and overweight are increasing globally, with affected individuals often experiencing health issues and reduced quality of life. The pathogenesis of obesity is complex and multifactorial, and effective solutions have been elusive. In this Viewpoint, experts in the fields of medical therapy, adipocyte biology, exercise and muscle, bariatric surgery, genetics, and public health give their perspectives on current and future progress in addressing the rising prevalence of obesity.

Weight loss strategies, weight change, and type 2 diabetes in US health professionals: A cohort study.

BACKGROUND: Weight loss is crucial for disease prevention among individuals with overweight or obesity. This study aimed to examine associations of weight loss strategies (WLSs) with weight change and type 2 diabetes (T2D) risk among US health professionals. METHODS AND FINDINGS: This study included 93,110 participants (24 to 60 years old; 11.6% male) from the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS) cohorts who were free of T2D, cardiovascular disease, and cancer at baseline (1988 for NHS/HPFS and 1989 for NHSII) for analyses of weight change and 104,180 (24 to 78 years old; 14.2% male) for T2D risk assessment. WLSs used to achieve an intentional weight loss of 4.5+ kg were collected in 1992 (NHS/HPFS)/1993 (NHSII) and grouped into 7 mutually exclusive categories, including low-calorie diet, exercise, low-calorie diet and exercise, fasting, commercial weight loss program (CWLP), diet pills, and FCP (selected at least 2 methods from fasting, CWLP, and pill). The reference group was participants who did not attempt to lose weight. Generalized estimating equations and Cox regression were applied to estimate up to 10-year weight change trajectory and incident T2D risk through 2016 (NHS/HPFS)/2017 (NHSII), respectively. The associations of WLSs with weight change and T2D risk were differential by baseline body weight (Pinteraction < 0.01). Among individuals with obesity, all WLSs tended to associate with less weight gain [ranging from -4.2% (95% confidence interval (CI), -5.1% to -3.2%; P < 0.001) for exercise to -0.3% (-1.2% to 0.7%; P > 0.99) for FCP] and a lower T2D risk [hazard ratios (HRs) ranging from 0.79 (0.66 to 0.95; P = 0.04) for exercise to 0.87 (0.66 to 1.13; P = 0.30) for pill]. Such a pattern was less clear among overweight individuals: the difference of weight change varied from -2.5% (-3.0% to -2.1%; P < 0.001) for exercise to 2.0% (1.3% to 2.7%; P < 0.001) for FCP, and HRs of T2D varied from 0.91 (0.77 to 1.07; P = 0.29) for exercise to 1.42 (1.11 to 1.81; P = 0.02) for pill. The pattern was further inverted among lean individuals in that weight change ranged from -0.4% (-0.6% to -0.1%; P = 0.02) for exercise to 3.7% (3.1% to 4.3%; P < 0.001) for FCP, and the HRs of T2D ranged from 1.09 (0.91 to 1.30; P = 0.33) for exercise to 1.54 (1.13 to 2.10; P = 0.008) for pill. Approximately 15.6% to 46.8% of the association between WLSs and the T2D risk was attributed to weight changes. This study was limited by a single assessment of WLSs, heterogeneity within each WLS, and potential misclassification of the timing of weight loss and weight regain. CONCLUSIONS: The current study showed that individuals with obesity who attempted to lose weight, regardless of the WLSs used, tended to gain less body weight and have a lower diabetes risk. In contrast, lean individuals who intentionally lost weight tended to gain more weight and have a higher diabetes risk. These data support the notion that intentional weight loss may not be beneficial for lean individuals and the use of WLSs for achieving weight loss shall be guided by medical indications only.

Comparative Safety and Effectiveness of Roux-en-Y Gastric Bypass and Sleeve Gastrectomy for Weight Loss and Type 2 Diabetes Across Race and Ethnicity in the PCORnet Bariatric Study Cohort.

Importance: Bariatric surgery is the most effective treatment for severe obesity; yet it is unclear whether the long-term safety and comparative effectiveness of these operations differ across racial and ethnic groups. Objective: To compare outcomes of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) across racial and ethnic groups in the National Patient-Centered Clinical Research Network (PCORnet) Bariatric Study. Design, Setting, and Participants: This was a retrospective, observational, comparative effectiveness cohort study that comprised 25 health care systems in the PCORnet Bariatric Study. Patients were adults and adolescents aged 12 to 79 years who underwent a primary (first nonrevisional) RYGB or SG operation between January 1, 2005, and September 30, 2015, at participating health systems. Patient race and ethnicity included Black, Hispanic, White, other, and unrecorded. Data were analyzed from July 1, 2021, to January 17, 2022. Exposure: RYGB or SG. Outcomes: Percentage total weight loss (%TWL); type 2 diabetes remission, relapse, and change in hemoglobin A1c (HbA1c) level; and postsurgical safety and utilization outcomes (operations, interventions, revisions/conversions, endoscopy, hospitalizations, mortality, 30-day major adverse events) at 1, 3, and 5 years after surgery. Results: A total of 36 871 patients (mean [SE] age, 45.0 [11.7] years; 29 746 female patients [81%]) were included in the weight analysis. Patients identified with the following race and ethnic categories: 6891 Black (19%), 8756 Hispanic (24%), 19 645 White (53%), 826 other (2%), and 783 unrecorded (2%). Weight loss and mean reductions in HbA1c level were larger for RYGB than SG in all years for Black, Hispanic, and White patients (difference in 5-year weight loss: Black, -7.6%; 95% CI, -8.0 to -7.1; P < .001; Hispanic, -6.2%; 95% CI, -6.6 to -5.9; P < .001; White, -5.9%; 95% CI, -6.3 to -5.7; P < .001; difference in change in year 5 HbA1c level: Black, -0.29; 95% CI, -0.51 to -0.08; P = .009; Hispanic, -0.45; 95% CI, -0.61 to -0.29; P < .001; and White, -0.25; 95% CI, -0.40 to -0.11; P = .001.) The magnitude of these differences was small among racial and ethnic groups (1%-3% of %TWL). Black and Hispanic patients had higher risk of hospitalization when they had RYGB compared with SG (hazard ratio [HR], 1.45; 95% CI, 1.17-1.79; P = .001 and 1.48; 95% CI, 1.22-1.79; P < .001, respectively). Hispanic patients had greater risk of all-cause mortality (HR, 2.41; 95% CI, 1.24-4.70; P = .01) and higher odds of a 30-day major adverse event (odds ratio, 1.92; 95% CI, 1.38-2.68; P < .001) for RYGB compared with SG. There was no interaction between race and ethnicity and operation type for diabetes remission and relapse. Conclusions and Relevance: Variability of the comparative effectiveness of operations for %TWL and HbA1c level across race and ethnicity was clinically small; however, differences in safety and utilization outcomes were clinically and statistically significant for Black and Hispanic patients who had RYGB compared with SG. These findings can inform shared decision-making regarding bariatric operation choice for different racial and ethnic groups of patients.

Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models.

The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.

Association of Bariatric Surgery With Vascular Outcomes.

Importance: Bariatric surgical weight loss is associated with reduced cardiovascular mortality; however, the mechanisms underlying this association are incompletely understood. Objectives: To identify variables associated with vascular remodeling after bariatric surgery and to examine how sex, race, and metabolic status are associated with microvascular and macrovascular outcomes. Design, Setting, and Participants: This population-based longitudinal cohort included 307 individuals who underwent bariatric surgery. Participants were enrolled in the bariatric weight loss program at Boston Medical Center, a large, multi-ethnic urban hospital, with presurgical and postsurgical assessments. Data were collected from December 11, 2001 to August 27, 2019. Data were analyzed in September 2019. Exposure: Bariatric surgery. Main Outcomes and Measures: Flow-mediated dilation (FMD) and reactive hyperemia (RH) (as measures of macrovascular and microvascular function, respectively) and clinical variables were measured preoperatively at baseline and at least once postoperatively within 12 months of the bariatric intervention. Results: A total of 307 participants with obesity (mean [SD] age, 42 [12] years; 246 [80%] women; 199 [65%] White; mean [SD] body mass index, 46 [8]) were enrolled in this study. Bariatric surgery was associated with significant weight loss and improved macrovascular and microvascular function across subgroups of sex, race, and traditional metabolic syndrome (mean [SD] pre- vs postsurgery weight: 126 [25] kg vs 104 [25] kg; P < .001; mean [SD] pre- vs postsurgery FMD: 9.1% [5.3] vs 10.2% [5.1]; P < .001; mean [SD] pre- vs postsurgery RH: 764% [400] vs 923% [412]; P < .001). Factors associated with change in vascular phenotype correlated most strongly with adiposity markers and several metabolic variables depending on vascular territory (eg, association of weight change with change in RH: estimate, -3.2; 95% CI, -4.7 to -1.8; association of hemoglobin A1c with change in FMD: estimate, -0.5; 95% CI, -0.95 to -0.05). While changes in macrovascular function among individuals with metabolically healthy obesity were not observed, the addition of biomarker assessment using high-sensitivity C-reactive protein plasma levels greater than 2 mg/dL identified participants with seemingly metabolically healthy obesity who had low-grade inflammation and achieved microvascular benefit from weight loss surgery. Conclusions and Relevance: The findings of this study suggest that bariatric intervention is associated with weight loss and favorable remodeling of the vasculature among a wide range of individuals with cardiovascular risk. Moreover, differences in arterial responses to weight loss surgery by metabolic status were identified, underscoring heterogeneity in physiological responses to adiposity change and potential activation of distinct pathological pathways in clinical subgroups. As such, individuals with metabolically healthy obesity represent a mixed population that may benefit from more refined phenotypic classification.

Approach to the Patient: Management of the Post-Bariatric Surgery Patient With Weight Regain.

CONTEXT: Weight regain (WR) after bariatric surgery is emerging as a common clinical problem due to the increase in the number of procedures performed. Early interventions are necessary to curtail the potential recurrence of comorbid conditions. However, it is often difficult to recognize WR early enough to introduce mitigating measures because there are no current guidelines for timely diagnosis and assessment of the severity of this condition. OBJECTIVE: We present a practical approach for the early recognition of WR, based on 11-year follow-up data from our multiethnic bariatric surgery patient population. METHODS: We classify WR according to the rate of increase in weight relative to nadir weight, normalized per 30-day interval. We also review pertinent literature about the etiologic factors contributing to WR after bariatric surgery. RESULTS: According to our algorithm, mild, moderate, and rapid WR are defined as weight increases of 0.2% to <0.5%, 0.5% to 1.0%, and more than 1.0% of nadir weight per 30 days, respectively. Treatment options, including dietary counseling, use of antiobesity medication, and consideration of surgical revision, are described. A case is presented to illustrate the utility of timely identification of WR and the importance of collaboration between bariatric surgeons, obesity medicine specialists, and dietitians. CONCLUSION: Our approach emphasizes the importance of regular long-term follow-up for all bariatric surgery patients.

The Mitigating Effect of Phentermine and Topiramate on Weight Regain After Roux-en-Y Gastric Bypass Surgery.

OBJECTIVE: Weight regain (WR) after Roux-en-Y gastric bypass surgery (RYGB) starts to occur 2 years after surgery, ultimately affecting at least 25% of patients. A limited number of studies have evaluated the impact of antiobesity medications (AOMs) on this phenomenon. METHODS: This study reviewed the electronic medical records of 1,196 patients who underwent RYGB between 2004 and 2015. WR was evaluated by comparing each patient's weight during subsequent postoperative office visits to nadir weight (lowest weight after RYGB, n = 760), taking into consideration the interval during which WR occurred. Patients who were prescribed AOMs and came to follow-up visits were classified as adherent users, whereas those who missed their follow-up visits were considered nonadherent. This study used a linear mixed model, Cox regression, and generalized equation estimator to determine the impact of AOMs on WR trajectory, hazard ratio for time to event, and odds ratio for repeated event occurrence, respectively. RESULTS: Despite the lack of a unified protocol for using AOMs, the three statistical models converged to show that phentermine and topiramate, used individually or in combination, can significantly reduce WR after RYGB. CONCLUSIONS: Phentermine and topiramate are effective in mitigating WR after RYGB. Further studies are needed to help ascertain optimal use of AOMs after bariatric surgery.

Mediating Role of Bone Marrow Lesions, Synovitis, Pain Sensitization, and Depressive Symptoms on Knee Pain Improvement Following Substantial Weight Loss.

OBJECTIVE: Massive weight loss leads to marked knee pain reduction in individuals with knee pain, but the reason for the reduction in pain is unknown. This study was undertaken to quantify the contribution of magnetic resonance imaging (MRI)-evidenced changes in pain-sensitive structures, bone marrow lesions (BMLs), and synovitis, and changes in pain sensitization or depressive symptoms, to knee pain improvement after substantial weight loss. METHODS: Morbidly obese patients with knee pain on most days were evaluated before bariatric surgery or medical weight management and at 1-year follow-up for BMLs and synovitis seen on MRI, the pressure pain threshold (PPT) at the patella and the right wrist, depressive symptoms (using the Center for Epidemiologic Studies Depression scale [CES-D]), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain survey. Natural-effects models were used to quantify the extent that achieving a minimum clinically important difference (MCID) of ≥18% on the WOMAC pain scale could be mediated by weight loss-induced changes in BMLs, synovitis, PPT, and depressive symptoms. RESULTS: Of 75 participants, 53.3% lost ≥20% of weight by 1 year. Of these, 75% attained the MCID for pain improvement, compared with 34.3% in those who had <20% weight loss. Mediation analyses suggested that, in those with at least 20% weight loss, the odds of pain improvement increased by 62%, 15%, and 22% through changes in patella PPT, wrist PPT, and CES-D, respectively, but pain improvement was not mediated by MRI changes in BMLs or synovitis. CONCLUSION: Weight loss-induced knee pain improvement is partially mediated by changes in pain sensitization and depressive symptoms but is independent of MRI changes in BMLs and synovitis.

Clinical Challenge: Patient With Severe Obesity BMI 46 kg/m2.

Obesity causes and exacerbates many disease processes and affects every organ system. Thus it is not surprising that clinical providers are often overwhelmed with the multitude of symptomatology upon initial presentation in patients with obesity. However, despite a "complicated medical history," a systematic, organized approach in obesity medicine utilizes a personalized-tailored treatment strategy coupled with understanding of the disease state, presence of comorbidities, contraindications, side effects, and patient preferences. Here, we present the case of a young patient with Class 3b severe obesity, several obesity-related complications, and extensive psychological history. Through synergistic and additive treatments (behavioral/nutritional therapy combined with anti-obesity pharmacotherapy and concurrent enrollment in our bariatric surgery program), the patient was able to achieve significant -30.5% total body weight loss with improvement of metabolic parameters. Though these results are not typical of all patients, we must emphasize the need to encompass all available anti-obesity therapies (lifestyle, pharmacotherapy, medical devices, bariatric surgery in monotherapy or combination) in cases of refractory or severe obesity, as we do similarly for other disease modalities such as refractory hypertension or poorly controlled Type 2 diabetes that requires robust escalation in therapy.

Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction.

Hyperinsulinemia is strongly associated with type 2 diabetes. Racial and ethnic minority populations are disproportionately affected by diabetes and obesity-related complications. This mini-review provides an overview of the genetic and environmental factors associated with hyperinsulinemia with a focus on racial and ethnic differences and its metabolic consequences. The data used in this narrative review were collected through research in PubMed and reference review of relevant retrieved articles. Insulin secretion and clearance are regulated processes that influence the development and progression of hyperinsulinemia. Environmental, genetic, and dietary factors are associated with hyperinsulinemia. Certain pharmacotherapies for obesity and bariatric surgery are effective at mitigating hyperinsulinemia and are associated with improved metabolic health. Hyperinsulinemia is associated with many environmental and genetic factors that interact with a wide network of hormones. Recent studies have advanced our understanding of the factors affecting insulin secretion and clearance. Further basic and translational work on hyperinsulinemia may allow for earlier and more personalized treatments for obesity and metabolic diseases.

Fat-Specific Protein 27 Regulation of Vascular Function in Human Obesity.

Background Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat-specific protein 27) is a lipid droplet-associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive FSP27 expression in human endothelial cells that is downregulated in association with visceral obesity. We sought to examine the functional role of FSP27 in the control of vascular phenotype. Methods and Results We biopsied paired subcutaneous and visceral fat depots from 61 obese individuals (body mass index 44±8 kg/m2, age 48±4 years) during planned bariatric surgery. We characterized depot-specific FSP27 expression in relation to adipose tissue microvascular insulin resistance, endothelial function and angiogenesis, and examined differential effects of FSP27 modification on vascular function. We observed markedly reduced vasodilator and angiogenic capacity of microvessels isolated from the visceral compared with subcutaneous adipose depots. Recombinant FSP27 and/or adenoviral FSP27 overexpression in human tissue increased endothelial nitric oxide synthase phosphorylation and nitric oxide production, and rescued vasomotor and angiogenic dysfunction (P<0.05), while siRNA-mediated FSP27 knockdown had opposite effects. Mechanistically, we observed that FSP27 interacts with vascular endothelial growth factor-A and exerts robust regulatory control over its expression. Lastly, in a subset of subjects followed longitudinally for 12±3 months after their bariatric surgery, 30% weight loss improved metabolic parameters and increased angiogenic capacity that correlated positively with increased FSP27 expression (r=0.79, P<0.05). Conclusions Our data strongly support a key role and functional significance of FSP27 as a critical endogenous modulator of human microvascular function that has not been previously described. FSP27 may serve as a previously unrecognized regulator of arteriolar vasomotor capacity and angiogenesis which are pivotal in the pathogenesis of cardiometabolic diseases linked to obesity.

Psychiatric adverse events and effects on mood with prolonged-release naltrexone/bupropion combination therapy: a pooled analysis.

BACKGROUND/OBJECTIVES: Prolonged-release (PR) naltrexone 32 mg/bupropion 360 mg (NB) is approved for chronic weight management as an adjunct to reduced-calorie diet and increased physical activity. Central nervous system-active medications have the potential to affect mood; therefore, post hoc analysis of clinical trial data was conducted to evaluate psychiatric adverse events (PAEs) and effects on mood of NB therapy versus placebo. SUBJECTS/METHODS: Data were pooled from 5 prospective, double-blind, randomized, placebo-controlled clinical trials (duration range, 24-56 weeks) of NB in subjects with overweight or obesity. PAEs were collected via AE preferred terms, organized into major subtopics (e.g., anxiety, depression, sleep disorders), and divided into category terms (e.g., anxiety, potential anxiety symptoms). Additionally, the Inventory of Depressive Symptomatology Self Report (IDS-SR; score range 0-84) and the Columbia Classification Algorithm of Suicide Assessment (C-CASA) evaluated treatment-emergent depressive/anxiety symptoms and suicidal behavior/ideation, respectively. RESULTS: Baseline characteristics and comorbidities were comparable for placebo (n = 1515) and NB (n = 2545). Most common PAEs in the NB group (using category grouping; NB vs placebo) were sleep disorders (12.7 vs 7.9%, P < 0.001), anxiety (5.4 vs 3.3%, P = 0.029), and depression (1.8 vs 2.7%, P = 0.014); PAEs were more frequent during dose escalation and generally mild or moderate. Mean (SD) changes in IDS-SR total score from baseline to endpoint were small in both groups: 0.13 (5.83) for NB and -0.45 (5.65) for placebo. Retrospective AE categorization via C-CASA confirmed no completed suicides, suicide attempts, or preparatory acts toward imminent suicidal behavior. CONCLUSIONS: This large pooled analysis of 5 clinical trials provides additional safety information about the NB PAE profile. Anxiety and sleep disorder-related PAEs were more frequent with NB versus placebo but were mostly mild to moderate and generally occurred early. Depression-related PAEs were less common with NB than placebo, and NB was not associated with suicidal ideation or behavior in this patient population.

Clinical Considerations Regarding the Use of Obesity Pharmacotherapy in Adolescents with Obesity.

A growing number of youth suffer from obesity and in particular severe obesity for which intensive lifestyle intervention does not adequately reduce excess adiposity. A treatment gap exists wherein effective treatment options for an adolescent with severe obesity include intensive lifestyle modification or metabolic and bariatric surgery while the application of obesity pharmacotherapy remains largely underutilized. These youth often present with numerous obesity-related comorbid diseases, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, obstructive sleep apnea, nonalcoholic fatty liver disease, musculoskeletal problems, and psychosocial issues such as depression, anxiety, and social stigmatization. Current pediatric obesity treatment algorithms for pediatric primary care providers focus primarily on intensive lifestyle intervention with escalation of treatment intensity through four stages of intervention. Although a recent surge in the number of Food and Drug Administration-approved medications for obesity treatment has emerged in adults, pharmacotherapy options for youth remain limited. Recognizing treatment and knowledge gaps related to pharmacological agents and the urgent need for more effective treatment strategies in this population, discussed here are the efficacy, safety, and clinical application of obesity pharmacotherapy in youth with obesity based on current literature. Legal ramifications, informed consent regulations, and appropriate off-label use of these medications in pediatrics are included, focusing on prescribing practices and prescriber limits.

Body Weight Considerations in the Management of Type 2 Diabetes.

Obesity is one of the main risk factors for type 2 diabetes (T2D), representing a major worldwide health crisis. Modest weight-loss (≥ 5% but < 10%) can minimize and reduce diabetes-associated complications, and significant weight-loss can potentially resolve disease. Treatment guidelines recommend that intensive lifestyle interventions, pharmacologic therapy, and/or metabolic surgery be considered as options for patients with T2D and obesity. The benefits and risks of such interventions should be evaluated in the context of their weight-loss potential, ability to sustain weight change, side effect profile, and costs. Antihyperglycemia therapies have considerable effects on patient weight, prompting careful consideration of weight-loss or weight-neutral therapies for patients with T2D who also have obesity. Metformin, sodium glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), α-glucosidase inhibitors, and amylin mimetics promote weight-loss. Dipeptidyl peptidase-4 inhibitors and fixed-ratio insulin/GLP-1 RA combination therapies (IDegLira, iGlarLixi) appear to be weight-neutral. Thiazolidinediones, insulin secretagogues (sulfonylureas, meglitinides), and insulins are associated with weight gain. Sulfonylureas are additionally associated with a higher risk of serious hypoglycemia from hyperinsulinemia, making them less suitable for the treatment of patients who are overweight or have obesity. Patients are often overtitrated on basal insulin, resulting in an increased risk of hypoglycemia and weight gain without achieving glycemic goals. Given these observations, the effects of antihyperglycemia agents on weight should be considered when individualizing T2D therapy.Funding: Sanofi US, Inc.