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General Reviews

Obesity Pathogenesis: An Endocrine Society Scientific Statement (2017) Schwartz, Seeley, Zeltser, Drewnowski, Ravussin, Redman, Leibel

Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight.
We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this “upward setting” or “resetting” of the defended level of body-fat mass, whether inherited or acquired.
The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences.

Sugar sweetened beverages (SSBs)

Intake of sugar-sweetened beverages and weight gain: a systematic review. (2006) Malik, Schulze MB, Hu FB.

Thirty publications (15 cross-sectional, 10 prospective, and 5 experimental) were selected on the basis of relevance and quality of design and methods. Findings from large cross-sectional studies, in conjunction with those from well-powered prospective cohort studies with long periods of follow-up, show a positive association between greater intakes of SSBs and weight gain and obesity in both children and adults. Findings from short-term feeding trials in adults also support an induction of positive energy balance and weight gain by intake of sugar-sweetened sodas, but these trials are few. :::A school-based intervention found significantly less soft-drink consumption and prevalence of obese and overweight children in the intervention group than in control subjects after 12 mo, and a recent 25-week randomized controlled trial in adolescents found further evidence linking SSB intake to body weight.
The weight of epidemiologic and experimental evidence indicates that a greater consumption of SSBs is associated with weight gain and obesity. Although more research is needed, sufficient evidence exists for public health strategies to discourage consumption of sugary drinks as part of a healthy lifestyle.


Effects of soft drink consumption on nutrition and health: a systematic review and meta-analysis. (2007) Vartanian, Schwartz MB, Brownell KD.

In a meta-analysis of 88 studies, we examined the association between soft drink consumption and nutrition and health outcomes. We found clear associations of soft drink intake with increased energy intake and body weight. Soft drink intake also was associated with lower intakes of milk, calcium, and other nutrients and with an increased risk of several medical problems (e.g., diabetes).
Study design significantly influenced results: larger effect sizes were observed in studies with stronger methods (longitudinal and experimental vs cross-sectional studies). Several other factors also moderated effect sizes (e.g., gender, age, beverage type). Finally, studies funded by the food industry reported significantly smaller effects than did non-industry-funded studies. Recommendations to reduce population soft drink consumption are strongly supported by the available science.


Sugar-sweetened beverages and genetic risk of obesity. (2012) Qi Q et al.

In the NHS and HPFS cohorts, the genetic association with BMI was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake. In the combined cohorts, the increases in BMI per increment of 10 risk alleles were 1.00 for an intake of less than one serving per month, 1.12 for one to four servings per month, 1.38 for two to six servings per week, and 1.78 for one or more servings per day (P<0.001 for interaction).
For the same categories of intake, the relative risks of incident obesity per increment of 10 risk alleles were 1.19 (95% confidence interval [CI], 0.90 to 1.59), 1.67 (95% CI, 1.28 to 2.16), 1.58 (95% CI, 1.01 to 2.47), and 5.06 (95% CI, 1.66 to 15.5) (P=0.02 for interaction). In the WGHS cohort, the increases in BMI per increment of 10 risk alleles were 1.39, 1.64, 1.90, and 2.53 across the four categories of intake (P=0.001 for interaction); the relative risks for incident obesity were 1.40 (95% CI, 1.19 to 1.64), 1.50 (95% CI, 1.16 to 1.93), 1.54 (95% CI, 1.21 to 1.94), and 3.16 (95% CI, 2.03 to 4.92), respectively (P=0.007 for interaction).
CONCLUSIONS: The genetic association with adiposity appeared to be more pronounced with greater intake of sugar-sweetened beverages.


A Trial of Sugar-free or Sugar-Sweetened Beverages and Body Weight in Children (2012) Janne C. de Ruyter et al

Masked replacement of sugar-containing beverages with non-caloric beverages reduced weight gain and fat accumulation in normal-weight children.
Children in the United States consume on average almost three times as many calories from sugar-sweetened beverages as the amount provided in our trial. We speculate that decreased consumption of such beverages might reduce the high prevalence of overweight in these children.


Sugar intake by type (added vs. naturally occurring) and physical form (liquid vs. solid) and its varying association with children's body weight, NHANES 2009-2014. (2018) Welsh JA, Wang Y, Figueroa J, Brumme C.


Dietary sugars, most of which are AS (added sugars), are a major contributor of calories in the diets of U.S. children. Only AS in non-dairy sources were associated with weight although the direction differed by the form consumed. AS in beverages were associated positively and those in foods were associated inversely with children's weight status.


Frequent Sugar-Sweetened Beverage Consumption and the Onset of Cardiometabolic Diseases: Cause for Concern? (2017) Deshpande G, Mapanga RF, Essop MF.

Recent data show that SSB consumption has increased globally, thus putting many at risk for the onset of weight gain, T2DM, hypertension, CVD, and other chronic illnesses. The mechanisms whereby such diseases progress are closely linked to insulin resistance, pancreatic β-cell dysfunction, visceral adiposity, dyslipidemia, and inflammation. The current mini-review evaluated recent literature (past decade) and shows that SSB consumption worsens the risk for MetS, T2DM, and CVD onset. However, there are limitations; for example, many do not take the sex and/or ethnicity of participants into account, although it is evident that such factors may contribute to the complexity of the results.
The short-term nature of numerous studies is also a problem as long-term effects can therefore only be projected or predicted. Together these data highlight the need for (1) well-designed basic and clinical studies to obtain a clearer picture, (2) further research into the molecular mechanisms underlying the development of such debilitating conditions, and (3) increased roll-out of educational programs to inform the general public of the harmful effects of high SSB intake.


Sugar-sweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk. (2010) Malik VS, Popkin BM, Bray GA, Després JP, Hu FB.

SSBs are the greatest contributor to added-sugar intake in the United States and are thought to promote weight gain in part because of incomplete compensation for liquid calories at subsequent meals. SSBs may also increase T2DM and cardiovascular risk independently of obesity as a potential contributor to a high dietary GL and increased fructose metabolism, leading to inflammation, insulin resistance, impaired β-cell function, and high blood pressure, as well as accumulation of visceral adiposity/ectopic fat and atherogenic dyslipidemia.
For these reasons and because they have little nutritional value, intake of SSBs should be limited, and SSBs should be replaced by healthy alternatives such as water.


Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes?: health be damned! Pour on the sugar. (2014) Bray GA, Popkin BM.

Meta-analyses and randomized clinical trials were used to evaluate outcomes of beverage and fructose intake. About 75% of all foods and beverages contain added sugar in a large array of forms. Consumption of soft drinks has increased fivefold since 1950. Meta-analyses suggest that consumption of sugar-sweetened beverages (SSBs) is related to the risk of diabetes, the metabolic syndrome, and cardiovascular disease.
Drinking two 16-ounce SSBs per day for 6 months induced features of the metabolic syndrome and fatty liver. Randomized controlled trials in children and adults lasting 6 months to 2 years have shown that lowering the intake of soft drinks reduced weight gain. Recent studies suggest a gene-SSB potential relationship. Consumption of calorie-sweetened beverages has continued to increase and plays a role in the epidemic of obesity, the metabolic syndrome, and fatty liver disease. Reducing intake of soft drinks is associated with less weight gain.


Cross-over studies underestimate energy compensation: The example of sucrose-versus sucralose-containing drinks. (2016) Nouf S.Gadah, Jeffrey M.Brunstrom, Peter J.Rogers

Taken together, these various results demonstrate unequivocally that sucrose consumed in a drink reduces subsequent energy intake. This effect, however, is not sufficient to prevent increased cumulative energy intake, even when measured using a parallel-groups design (non-significant increase of 58 kcal), and optimising the timing of the test-meal interval to coincide with the peak effect of the preload on blood glucose concentration.


Childhood Abuse and Trauma

Effects of childhood abuse on adult obesity: a systematic review and meta-analysis (2014)

Systematic searches of PubMed, PsycInfo, Medline and CINAHL resulted in 23 cohort studies (4 prospective, 19 retrospective) with n=112,708 participants, containing four abuse types (physical, emotional, sexual, general). Four studies reported dose-response effects. A random effects model was used to quantify effect sizes, meta-regression/subgroup analysis for identifying potential moderating variables and Egger's test for publication bias.
Adults who reported childhood abuse were significantly more likely to be obese (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.24-1.45, P<0.001). All four types of abuse were significantly associated with adult obesity: physical (OR: 1.28, 95% CI: 1.13-1.46), emotional (OR: 1.36, 95% CI: 1.08-1.71), sexual (OR: 1.31, 95% CI: 1.13-1.53) and general abuse (OR: 1.45, 95% CI: 1.25-1.69). Severe abuse (OR: 1.50, 95% CI: 1.27-1.77) was significantly more associated with adult obesity (P=0.043) compared with light/moderate abuse (OR: 1.13, 95% CI: 0.91-1.41). We found no significant effects of study design (prospective vs. retrospective, P=0.07), age (P=0.96) or gender (P=0.92). Publication bias was evident (Egger's test P=0.007), but effect sizes remained statistically significant in sensitivity analyses.
Childhood abuse was clearly associated with being obese as an adult, including a positive dose-response association. This suggests that adverse life experiences during childhood plays a major role in obesity development, potentially by inducing mental and emotional perturbations, maladaptive coping responses, stress, inflammation and metabolic disturbances.
Another detrimental effect of childhood abuse is a chronically elevated inflammatory response to stress, notably interleukin-6. The elevation in pro-inflammatory cytokines can be life-long with serious detrimental effects on health. Chronic stress, or inability to cope with lower level daily stressors, is also associated with elevated cortisol levels, which increase appetite and promote visceral obesity.
Elevated stress also increases cravings of palatable foods. A recent prospective analysis from the Nurses’ Health Study also found that women with greater post-traumatic stress disorder symptoms gained significantly more body weight during a 16-year follow-up


Child Maltreatment’s Heavy Toll The Need for Trauma-Informed Obesity Prevention (2015)

Emerging research has highlighted childhood maltreatment and other psychological traumas as risk factors for obesity and related comorbidities. Although the high rate of obesity in the U.S. affects the entire population, those with histories of maltreatment—making up at least 30% of the population —appear to be at greater risk.
Unfortunately, childhood maltreatment is often overlooked as a risk factor for adult obesity, and efforts to prevent and treat obesity under-utilize promising trauma-informed approaches. Likewise, clinical care for psychological trauma has unrealized potential as an opportunity for obesity prevention.
The aims of this paper are to: 1. raise awareness of the prevalence of childhood maltreatment; 2. present current evidence of the child maltreatment– obesity association; 3. highlight existing research on mechanisms; and 4. suggest areas for additional research, including traumainformed obesity interventions that warrant testing.
Although this paper focuses on childhood maltreatment, particularly physical and sexual abuse, the presented information is potentially relevant to other types of early trauma, such as community violence and peer bullying.


Childhood abuse and inflammatory responses to daily stressors (2012)

BACKGROUND:Childhood abuse leads to greater morbidity and mortality in adulthood. Dysregulated physiological stress responses may underlie the greater health risk among abused individuals.
PURPOSE: This study evaluated the impact of childhood abuse on inflammatory responses to naturalistically occurring daily stressors.
METHODS: In this cross-sectional study of 130 older adults, recent daily stressors and childhood abuse history were evaluated using the Daily Inventory of Stressful Events and the Childhood Trauma Questionnaire. Blood samples provided data on circulating interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP).
RESULTS: Childhood abuse history moderated IL-6 levels but not TNF-α and CRP responses to daily stressors. Individuals with a childhood abuse history who experienced multiple stressors in the past 24 h had IL-6 levels 2.35 times greater than those of participants who reported multiple daily stressors but no early abuse history.
CONCLUSION: Childhood abuse substantially enhances IL-6 responses to daily stressors in adulthood.


Childhood sexual abuse, depression, and family dysfunction in adult obese patients: a case control study (1993)

One hundred significantly overweight patients sequentially applying to a very low calorie diet (VLCD) program were interviewed to learn how the onset of obesity correlated with other life events. By comparison with a control group of 100 always-slender adults, the obese applicants were found to be different at a highly significant level in the prevalence of childhood sexual abuse, nonsexual childhood abuse, early parental loss, parental alcoholism, chronic depression, and marital family dysfunction in their own adult lives.
The obese patients commonly reported using obesity as a sexually protective device; many reported overeating to cope with emotional distress. Inquiry into depression, past sexual abuse, and past or present dysfunctional family life should be added to the current medical evaluation of all obese patients.
The resultant findings are likely to be relevant to their treatment, whether for obesity or for other medical conditions.


History of sexual abuse and obesity treatment outcome (1996)

In this study, clinical data from 22 obese women who reported a history of sexual abuse were compared to clinical data from 22 obese women who denied a history of sexual abuse. Subjects were matched for body mass index (BMI), sex, and age. All subjects were enrolled in a multidisciplinary outpatient hospital-based very-low-calorie diet (VLCD) weight-management program. Subjects completed a structured clinical interview, the Beck Depression Inventory (BDI), and the Weight Efficacy Life-Style Questionnaire (WEL).
Subjects with a history of sexual abuse lost significantly less weight and reported more episodes of non-adherence.
Possible explanations for these findings include both psychiatric distress and low weight self-efficacy. The difference between the groups in self-efficacy was greatest in situations involving negative affect or physical discomfort.


Does childhood sexual abuse predict young adult's BMI? A birth cohort study (2007)

OBJECTIVE: The objective was to identify the extent to which childhood sexual abuse (CSA) is associated with BMI and overweight status in young adulthood and to examine whether any associations differ by gender.
RESEARCH METHODS AND PROCEDURES: The Mater-University of Queensland Study of Pregnancy is a prospective birth cohort from a population-based sample involving 7223 singletons whose mothers were enrolled in the 1980s at the first antenatal visit. The present cohort consisted of a subgroup of 2461 young adults who had both self-reported CSA data and measured BMI at 21 years.
RESULTS: Of 1273 men, 10.5% reported non-penetrative and 7.5% reported penetrative CSA before age 16 years. Of 1305 women, 20.6% reported non-penetrative and 7.9% reported penetrative CSA by age 16 years. We found young women's BMI and the prevalence of overweight at age 21 were greater in those who experienced penetrative CSA. This association was robust to adjustment for a variety of potential confounders. However, there was no association between non-penetrative CSA and BMI in women and no association between either category of CSA and BMI in men. There was statistical evidence for a gender difference in the association of CSA with mean BMI at age 21 (p value for statistical interaction <0.01 in all models).
DISCUSSION: These findings suggest that among women, penetrative CSA is associated with greater BMI and increased odds of being overweight in later life, whereas in men, this association does not hold. This gender difference may reflect differences between women and men in the relationship between psychological trauma and body image or may be a chance subgroup finding.
It is unlikely that being overweight leads to CSA as the groups had similar BMI at age 5 years, and the association remained when we further adjusted the multi-variable models to include BMI at age 5. Mechanisms suggested for this association include abnormal patterns of eating, including binge eating, and obesity as an adaptive response by victims. Both of these mechanisms may also include behavioral and emotional changes in the child.


Childhood Maltreatment and BMI Trajectory: The Mediating Role of Depression (2017)

INTRODUCTION: Childhood maltreatment is associated with later obesity, but the underlying mechanisms are unknown. The objective of this study was to estimate the extent to which depression mediates the associations between childhood maltreatment and BMI in adolescence through adulthood.
METHODS: Data on a cohort of 13,362 adolescents in the National Longitudinal Study of Adolescent to Adult Health (Wave I [1994-1995] to Wave IV [2008-2009]) were analyzed in 2015-2016. Classes of maltreatment experienced prior to age 12 years were statistically identified using latent class analysis. Gender-stratified latent growth curve analysis was used to estimate total effects of maltreatment classes on latent BMI trajectory (aged 13-31 years) and indirect effects of maltreatment classes that occurred through latent depression trajectory (aged 12-31 years).
RESULTS: Four latent maltreatment classes were identified: high abuse and neglect; physical abuse dominant; supervisory neglect dominant; and no/low maltreatment. In girls, compared with no/low maltreatment, supervisory neglect dominant (coefficient=0.3, 95% CI=0.0, 0.7) and physical abuse dominant (coefficient=0.6, 95% CI=0.1, 1.2) maltreatment were associated with faster gain in BMI. Change in depression over time fully mediated the association of BMI slope with physical abuse dominant maltreatment, but not with supervisory neglect dominant maltreatment. In boys, high abuse and neglect maltreatment was associated with marginally greater BMI at baseline (coefficient=0.7, 95% CI= -0.1, 1.5); this association was not mediated by depression.
CONCLUSIONS: Although maltreatment was associated with depression and BMI trajectories from adolescence to adulthood, depression only mediated associations with physical abuse dominant maltreatment in girls.


Stress as a Common Risk Factor for Obesity and Addiction (2013)

Morning screening of fasting plasma glucose and insulin was assessed in a large subgroup of these healthy community volunteers, and homeostasis model assessment was calculated as an index of insulin resistance. We found that cumulative stress was associated with BMI-related changes in higher levels of glucose, insulin, and homeostasis model assessment. These data indicate stronger associations between cumulative total stress and metabolic dysfunction among individuals in higher compared with lower BMI categories. These findings are similar to previous research, indicating stronger effects of stress on increased substance use in individuals who are regular–heavy as compared with light or recreational users.
Together, these findings suggest that cumulative and repeated stress increases obesity risk and that individuals with higher BMIs might be more vulnerable to stress related food consumption and subsequent weight gain.
There is significant evidence suggesting potentially detrimental effects of stress on eating patterns (e.g., skipping meals, restraining intake, binging) and food preference. Stress can increase consumption of fast food, snacks, and calorie dense and HP foods, and stress has been associated with increased binge eating. The effects of stress might be different in lean as compared with obese individuals. Stress-driven eating has been found to be exacerbated in obese women, whereas stress-driven eating seems to have an inconsistent effect on food consumption in lean individuals.
Furthermore, changes in eating patterns might relate to carbohydrate metabolism and insulin sensitivity. In healthy lean women, binge eating increases fasting glucose, insulin response, and alters the diurnal pattern of leptin secretion. Irregular meal frequency has been found to increase insulin in response to a test meal after a period of irregular eating patterns, together, this research suggests that stress might promote irregular eating patterns and alter food preference and that overweight and obese individuals might be more vulnerable to such effects, possibly via weight-related adaptations in energy regulation and homeostasis.
Glucocorticoids increase plasma leptin and ghrelin levels, and ghrelin also increases with stress and is involved in regulating anxiety and mood. Furthermore, a number of hypothalamic neuropeptides—such as CRF, propriomelanocortin, the orexigenic neuropeptide Y (NPY), and agoutirelated peptide—as well as the melanocortin receptors involved in regulating the stress response also play a role in feeding (30).