ABC of obesity. Management: Part III--surgery.
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Bariatric Surgery↗
Biomedical subjects
John G Kral
Publications and source records attributed to John G Kral.
Effect of circulatory congestion on the components of pulmonary diffusing capacity in morbid obesity.
OBJECTIVE: Obese patients without clinically apparent heart disease may have a high output state and elevated total and central blood volumes. Central circulatory congestion should result in elevated pulmonary diffusing capacity (DLCO) and capillary blood volume (Vc) reflecting pulmonary capillary recruitment; however, the effect on membrane diffusion (Dm) is uncertain. We examined DLCO and its partition into Vc and Dm in 13 severely obese subjects (BMI = 51 +/- 14 kg/m2) without manifest cardiopulmonary disease before and after surgically induced weight loss. RESEARCH METHODS AND PROCEDURES: DLCO and its partition into Vc and Dm [referenced to alveolar volume (VA)] as described by Roughton and Forster, total body water by tritiated water, and fat distribution by waist-to-hip ratio were performed. RESULTS: Despite normal DLCO (mean 98 +/- 16% predicted), Vc/VA was increased (mean 118 +/- 30% predicted), and Dm/VA was reduced (mean 77 +/- 34% predicted). Nine of 13 subjects were restudied after weight loss (mean 52 +/- 43 kg); Vc/VA decreased to 89 +/- 18% predicted (p = 0.01), and Dm/VA increased to 139 +/- 30% predicted (p < 0.01). Increasing total body water was associated with both increasing Vc (r = 0.74, p = 0.01) and increasing waist-to-hip ratio (r = 0.65, p = 0.02), indicating that circulatory congestion increases with increasing central obesity. DISCUSSION: Severely obese subjects without manifest cardiopulmonary disease may have increased Vc indicating central circulatory congestion and reduced Dm suggesting associated alveolar capillary leak, despite normal DLCO. Reversibility with weight loss is in accord with reversibility of the hemodynamic abnormalities of obesity.
Adolescent↗
Maternal-infant response to variable foraging demand in nonhuman primates: effects of timing of stressor on cerebrospinal fluid corticotropin-releasing factor and circulating glucocorticoid concentrations.
The maternal stress response may vary as a function of infant developmental phase. Using a median split, 13 bonnet macaque (M. radiata) mother-infant dyads were exposed to early initiation of variable foraging demand (VFD), a prolonged stressor, whereas 11 dyads were exposed to late VFD onset. Cerebrospinal fluid (CSF) and plasma samples were obtained from mothers and infants prior to and following VFD. Increases in maternal CSF corticotropin-releasing factor (CRF) concentrations were evident in response to late, but not early, VFD. Mothers exhibited either increased or decreased cortisol concentrations in response to VFD. However, absolute cortisol change was greater in early versus late VFD. Timing of the VFD stressor differentially affects maternal neuroendocrine response, with potential implications for the offspring's developmental trajectory.
Agonistic Behavior↗
Poverty, food insecurity, and obesity in children.
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Child↗
Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years.
OBJECTIVE: Our aim was to compare the prevalence of obesity in 172 children who were aged 2 to 18 years and born to 113 obese mothers (BMI: 31 +/- 9 kg/m2) with substantial weight loss after biliopancreatic bypass surgery with 45 same-age siblings who were born before maternal surgery (mothers' BMI: 48 +/- 8 kg/m2) and with current population standards. METHODS: In this case series, with >88% follow-up in a tertiary referral center, cross sectional office chart and telephone data on childhood and adolescent weights were transformed to z scores. RESULTS: After maternal surgery, the prevalence of obesity in the offspring decreased by 52% and severe obesity by 45.1%, with no increase in the prevalence of underweight. The z score reduction in obesity was gender specific, with boys reducing from 1.4 +/- 1.3 before to 0.57 +/- 1.7 after maternal surgery, corrected for birth order. The difference was not significant in girls (0.8 +/- 1.3 vs 0.8 +/- 1.2). Among children of both genders who were aged 6 to 18 years of age and born after maternal surgery, the prevalence of overweight was reduced to population levels. CONCLUSIONS: Contrary to outcomes after intrauterine under- and overnutrition, the prevalence of overweight and obesity in children of mothers with large voluntary postsurgical weight loss was similar to that in the general population, with no increase in underweight. The results demonstrate the importance of potentially modifiable epigenetic factors in the cause of obesity.
Adolescent↗
The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy.
The nuclear factor kappaB (NFkappaB) superfamily of eukaryotic transcription factors plays an important role in carcinogenesis. NF-kappaB and its regulators are linked to various signal transduction pathways as well as transcriptional activation events that mediate critical stages of cell proliferation. These intracellular signaling processes are thought to regulate chromatin structure to accommodate transcription, apoptosis, cell-cycle control, and cell transformation. In this capacity, uncontrolled or aberrant NF-kappaB activity may, in part, be responsible for breast cancer progression. Constitutive NF-kappaB expression may predict the metastatic potential of breast tumors, indicating early use of adjuvant therapy and suggesting NF-kappaB inhibition as a novel treatment. In this review, we discuss the regulatory mechanisms and physiological significance of NF-kappaB activation, and highlight recent advances in the development of NF-kappaB as an integral mediator of mammary carcinogenesis.
Animals↗
Patient selection and the physiology of gastrointestinal antiobesity operations.
Antiobesity surgery largely is "behavioral surgery"--the results rely on behavioral factors more than on the technical performance of the procedure. Therefore, patient selection and pre- and postoperative patient education are critical for outcome. The operations rely on mechanical and biochemical mechanisms, such as: (1)limiting food consumption through restriction by activating satiety or nimiety; (2) increasing or decreasing appetitive gastrointestinal peptides; and (3) reducing substrate stores by way of malabsorption or increased thermogenesis to ensure weight loss. The balance between physiologic mechanisms that promote weight loss and motivational factors that cause maladaptive eating is the greatest challenge to effective surgical treatment of obesity.
Body Mass Index↗
Synchronized maternal-infant elevations of primate CSF CRF concentrations in response to variable foraging demand.
BACKGROUND: The study of environment-gene interactions during neurodevelopment may facilitate our understanding of the origins of psychiatric disorders. Environmental contribution to the neurobiology of psychopathology is perhaps most relevant during infancy, where vulnerability to early-life stressors is particularly evident. OBJECTIVES: In the current study, we wished to examine if central corticotropin-releasing factor (CRF) would provide a plausible biological vehicle for synchronized increases in mothers and their infant. METHODS: Twenty-four mother-infant bonnet macaques (Macaca radiata) dyads, of known age and weight served as subjects. The subjects were group-housed in four pens of 5-7 dyads each, stabilized for several weeks prior to the study period. Although adequate food was always available, mothers faced uncertainty of food availability for 16 weeks within the first year of infant life, through a procedure dubbed "variable foraging demand" (VFD). Pre- and post-VFD cerebrospinal fluid (CSF) samples were obtained simultaneously on mothers and infants. RESULTS: Maternal CSF CRF concentrations exhibited a significant mean elevation of 26% from pre-VFD to post-VFD; there was no effect of number of days postpartum on maternal pre-VFD CSF CRF levels. There was a significant mean increase (45%) in infant CSF CRF concentrations over the 16-week period of the VFD paradigm. No infant sex differences were evident. Post-VFD minus pre-VFD differences in infant CSF CRF concentrations were positively correlated (r = .52; N = 16; P = .0384) with the magnitude of maternal CRF response to VFD, providing evidence of synchronized CSF CRF expression by the dyad. CONCLUSION: This parallel response within the dyad suggests, as one testable hypothesis, that maternal responsivity to the stress of the VFD condition is "communicated" between mother and infant via a CRF-mediated mechanism. The VFD stressor produces a parallel activation of the central CRF system in both mothers and their infants.
Animals↗
Early appearance of the metabolic syndrome in socially reared bonnet macaques.
Among 250 laboratory-born bonnet macaques living in social groups and maintained on commercial monkey chow, we measured weight, crown-rump length, sagittal abdominal diameter (SAD), and fasting serum insulin, glucose, triglycerides, high-density lipoproteins, low-density lipoproteins, and total cholesterol. Body mass index (BMI = weight/crown-rump length(2)), and insulin resistance determined by the insulin/glucose ratio (IGR) and homeostasis model assessment, were measured. We defined the metabolic syndrome using a composite score based on morphometry, insulin resistance, and serum lipid levels, analogous to clinical criteria. Elevated BMI was associated with significantly greater SAD, insulin, IGR, homeostasis model assessment, and triglycerides. Among 120 adult monkeys aged 5-17 yr, males (n = 48) had higher BMI, SAD, insulin, and IGR levels than females, independent of age. Sixteen of 113 adult monkeys and five of 36 peripubertal subjects, aged 3-4 yr (14%), met our criteria for the metabolic syndrome, as did four of 12 monkeys, aged 20-28 yr. Markers of the metabolic syndrome are present by 3-4 yr of age in our colony and are observed across the life span in the absence of conventional obesifying interventions. Socially reared and housed bonnet macaques may provide a useful model for studying the pathogenesis, prevention, and treatment of the metabolic syndrome.
Animals↗
Gene variants and binge eating as predictors of comorbidity and outcome of treatment in severe obesity.
Melanocortin-4 receptor gene (MC4R) variants are associated with obesity and binge eating disorder (BED), whereas the more prevalent proopiomelanocortin (POMC) and leptin receptor gene (LEPR) mutations are rarely associated with obesity or BED. The complete coding regions of MC4R, POMC, and leptin-binding domain of LEPR were comparatively sequenced in 300 patients (233 women and 67 men; mean +/- SEM age, 42 +/- 1 years; mean +/- SEM body mass index, 43.5 +/- 0.3 kg/m2) undergoing laparoscopic gastric banding. Eating behavior, esophagogastric pathology, metabolic syndrome prevalence, and postoperative weight loss and complications were retrospectively compared between carriers and noncarriers of gene variants with and without BED during 36 +/- 3-month follow-up. Nineteen patients (6.3%) carried 8 MC4R variants, 144 (48.0%) carried 13 POMC variants, and 247 (82.3%) carried 11 LEPR variants. All MC4R variant carriers had BED, compared with 18.1% of noncarriers (P < 0.001). BED rates were similar among POMC and LEPR variant carriers and noncarriers. Gastroscopy revealed more erosive esophagitis in bingers than in nonbingers before and after banding (P < 0.04), regardless of genotype. MC4R variant carriers lost less weight (P=0.003), showed less improvement in metabolic syndrome (P < 0.001), had dilated esophagi (P < 0.001) and more vomiting (P < 0.05), and had fivefold more gastric complications (P < 0.001) than noncarriers. Overall outcome was poorest in MC4R variant carriers, better in noncarriers with BED (P < 0.05), and best in noncarriers without BED (P < 0.001). MC4R variants influence comorbidities and treatment outcomes in severe obesity.
Adult↗
Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis.
BACKGROUND: Both weight loss and gastrointestinal surgery for obesity can cause liver disease, making their role in the treatment of obesity-related liver disease controversial. METHODS: Six hundred eighty-nine severely obese women (n=551) and men (n=138), BMI=47+/-9 kg.m(-2) (mean+/-SD), without known liver disease, underwent biliopancreatic diversion (BPD) with liver biopsy. Fourteen patients (2%) had cryptogenic cirrhosis, 11 of whom underwent multiple repeat biopsies. After 38+/-18 kg weight loss, 104 of the 689 patients underwent routine second biopsies during reoperations 41+/-25 months after BPD. All biopsy specimens were graded for steatosis, fibrosis, and inflammation by a blinded hepatopathologist. RESULTS: All 689 patients lost weight accompanied by improvements in the metabolic syndrome. Among the 104 patients who underwent reoperation, severe fibrosis (grade 3-5) decreased in 28 whereas mild fibrosis (grade 1-2) appeared in 42. Increased fibrosis was related to low-normal serum albumin, uncontrolled diarrhea, low intake of alcohol, and menopausal status. Fibrosis and inflammation decreased over time (P<.01). The 11 patients with cirrhosis exhibited decreased fibrosis from a mean grade 5 to grade 3, as well as reduced inflammation, Mallory bodies, and glycogenated nuclei. Seven patients had disappearance and 2 regression of nodules and fibrous bridging. CONCLUSIONS: The metabolic syndrome of obesity is a determinant of liver fibrosis and cirrhosis, treatable by substantial weight loss after malabsorptive surgery.
Adult↗
Preventing and treating obesity in girls and young women to curb the epidemic.
Obesity and its serious comorbidities, type 2 diabetes, coronary heart disease, hypertension, and dyslipidemia, have reached epidemic proportions in adults and children. Female obesity is more prevalent and, thus, has greater epidemiological importance: mothers transmit the disease epigenetically and genetically. Maternal obesity affects maternal health, pregnancy outcome, and fetal, neonatal, childhood, and ultimately adult morbidity and mortality. Obesity is easy to diagnose, as are most of its risk factors, yet very little progress has been made in preventing the disease. During a brief period of rapid early growth, there is imprinting of antecedents of adult obesity and obesity-related disease. Because of the rapidity of this early growth and the relative brevity of the critical period, early recognition and prompt intervention are necessary and possibly sufficient to prevent the development of obesity. Identification of inappropriate rapid weight gain through frequent weighing should trigger immediate adjustment of energy intake, a simple intervention in bottle-fed infants, the ones at greatest risk for becoming obese. This review presents a step-care strategy with fail-safe action levels starting with maternal education and diet, exercise, and behavior modification for mother and child and progressing to drug treatment and, in selected cases, laparoscopic surgery for young women of childbearing age in whom other measures have failed. This approach is predicated on the assumption that careful monitoring and responsive supplementation of potential deficiencies is easier to achieve, more cost-effective, and safer than effectively treating manifest obesity and its comorbidities in adults.
Adolescent↗
Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa.
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Animals↗
Ghrelin: integrative neuroendocrine peptide in health and disease.
OBJECTIVE: Ghrelin is a novel gastric hormone recognized in 1999 as a mediator of growth hormone release. Since growth hormone is anabolic, an important function of ghrelin may be to coordinate energy needs with the growth process. Newly discovered biologic roles of ghrelin imply that it may have other important physiological functions as well. This is a review of recent clinically relevant, yet less well-known, physiologic actions of ghrelin. SUMMARY BACKGROUND DATA: Ghrelin has profound orexigenic, adipogenic, and somatotrophic properties, increasing food intake and body weight. Secreted predominantly from the stomach, ghrelin is the natural ligand for the growth hormone secretagogue receptor in the pituitary gland, thus fulfilling criteria of a brain-gut peptide. The brain-gut axis is the effector of anabolism by regulating growth, feeding, and metabolism via vagal afferents mediating ghrelin signaling. However, the wide tissue distribution of ghrelin suggests that it may have other functions as well. METHODS: Systematic literature review of all PubMed citations between 1999 and August 2003 focusing on clinically relevant biochemical and physiological characteristics of ghrelin. RESULTS: Ghrelin is an important component of an integrated regulatory system of growth and metabolism acting via the vagus nerve, and is implicated in a variety of altered energy states such as obesity, eating disorders, neoplasia, and cachexia. It also enhances immune responses and potentially down-regulates anti-inflammatory molecules. Ghrelin's role as a brain-gut peptide emphasizes the significance of afferent vagal fibers as a major pathway to the brain, serving the purpose of maintaining physiologic homeostasis. CONCLUSIONS: The discovery of ghrelin has increased our understanding of feeding regulation, nutritional homeostasis, and metabolic processes. Further characterization of ghrelin's functions will likely generate new pharmacological approaches to diagnose and treat different disease entities including those related to the over-nutrition of obesity and the catabolic response to surgical trauma.
Brain↗
Outcome of pregnancies after biliopancreatic diversion.
BACKGROUND: Severe obesity has deleterious effects on fertility and pregnancy outcomes. Although surgery is the best long-term treatment for severe obesity, there is a risk of gestational undernutrition in operated mothers because bariatric surgery reduces nutrient availability. This is a follow-up report of our initial findings regarding pregnancy and neonatal outcomes in biliopancreatic diversion (BPD) patients, with addition of a new cohort of children born to mothers after BPD. METHODS: All women (n = 916) who had successfully undergone BPD in our hospital were mailed a questionnaire containing multiple-choice and essay questions concerning gynecologic and obstetric history, and pregnancy and neonatal outcomes in both preoperative and postoperative pregnancies. Patients operated between 1984 and 1995 (n = 568) were mailed an additional questionnaire regarding children's weight and height progress, and school performance. Perinatal records from our patients' obstetric clinics were also reviewed. RESULTS: The questionnaire was completed by 783 women (85.5%). 251 postoperative pregnancies in 132 women resulted in 166 infants by 109 mothers. 47.0% of patients who were unable to become pregnant preoperatively were successful postoperatively. 90 out of 109 women (82.6%) reported an appropriate weight gain (9.1 +/- 5.9 kg) during postoperative pregnancies. The incidence of fetal macrosomia decreased from 34.8 to 7.7%, with a concomitant increase in normal-weight babies from 62.1 to 82.7%. The elevated miscarriage rate (26.0%) in these obese women persisted after surgery. CONCLUSION: Major weight loss following BPD improves the reproductive function of severely obese women. BPD provides major beneficial effects for both mother and child, including normalization of gestational weight changes, reduction of fetal macrosomia, and normalization of the infant's birth-weight. Our results speak in favor of delaying pregnancy in obese women until after the substantial surgical weight loss has occurred.
Adolescent↗
Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.
BACKGROUND: Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity. METHODS: We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the alpha melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [+/-SE] age, 41.0+/-0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1+/-2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7+/-2.0 years; body-mass index, 21.6+/-0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected. RESULTS: Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha melanocyte-stimulating hormone. CONCLUSIONS: Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior.
Adolescent↗
Adipose tissue quantification by imaging methods: a proposed classification.
Recent advances in imaging techniques and understanding of differences in the molecular biology of adipose tissue has rendered classical anatomy obsolete, requiring a new classification of the topography of adipose tissue. Adipose tissue is one of the largest body compartments, yet a classification that defines specific adipose tissue depots based on their anatomic location and related functions is lacking. The absence of an accepted taxonomy poses problems for investigators studying adipose tissue topography and its functional correlates. The aim of this review was to critically examine the literature on imaging of whole body and regional adipose tissue and to create the first systematic classification of adipose tissue topography. Adipose tissue terminology was examined in over 100 original publications. Our analysis revealed inconsistencies in the use of specific definitions, especially for the compartment termed "visceral" adipose tissue. This analysis leads us to propose an updated classification of total body and regional adipose tissue, providing a well-defined basis for correlating imaging studies of specific adipose tissue depots with molecular processes.
Adipose Tissue↗
Research considerations in obesity surgery.
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Age Factors↗