background The influence of excess body weight on the risk of death from cancer has not been fully characterized. methods In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. results The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin’s lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. conclusions Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites.

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Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.

Summary—In 1995 the American College of Sports Medicine and the Centers for Disease Control and Prevention published national guidelines on Physical Activity and Public Health The Committee on Exercise and Cardiac Rehabilitation of the American Heart Association endorsed and supported these recommendations The purpose of the present report is to update and clarify the 1995 recommendations on the types and amounts of physical activity needed by healthy adults to improve and maintain health Development of this document was by an expert panel of scientists, including physicians, epidemiologists, exercise scientists, and public health specialists This panel reviewed advances in pertinent physiologic, epidemiologic, and clinical scientific data, including primary research articles and reviews published since the original recommendation was issued in 1995 Issues considered by the panel included new scientific evidence relating physical activity to health, physical activity recommendations by various organizations in the interim, and communications issues Key points related to updating the physical activity recommendation were outlined and writing groups were formed A draft manuscript was prepared and circulated for review to the expert panel as well as to outside experts Comments were integrated into the final recommendation Primary Recommendation—To promote and maintain health, all healthy adults aged 18 to 65 yr need moderate-intensity aerobic (endurance) physical activity for a minimum of 30 min on five days each week or vigorous-intensity aerobic physical activity for a minimum of 20 min on three days each week [I (A)] Combinations of moderate- and vigorous-intensity activity can be performed to meet this recommendation [IIa (B)] For example, a person can meet the recommendation by walking briskly for 30 min twice during the week and then jogging for 20 min on two other days Moderate-intensity aerobic activity, which is generally equivalent to a brisk walk and noticeably accelerates the heart rate, can be accumulated toward the 30-min minimum by performing bouts each lasting 10 or more minutes [I (B)] Vigorous-intensity activity is exemplified by jogging, and causes rapid breathing and a substantial increase in heart rate In addition, every adult should perform activities that maintain or increase muscular strength and endurance a minimum of two days each week [IIa (A)] Because of the dose-response relation between physical activity and health, persons who wish to further improve their personal fitness, reduce their risk for chronic diseases and disabilities or prevent unhealthy weight gain may benefit by exceeding the minimum recommended amounts of physical activity [I (A)] (Circulation 2007;116:1081-1093)

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Physical Activity and Public Health Updated Recommendation for Adults From the American College of Sports Medicine and the American Heart Association

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Obesity as a medical problem

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

The hormone resistin links obesity to diabetes

Summary: In 1995 the American College of Sports Medicine and the Centers for Disease Control and Prevention published national guidelines on Physical Activity and Public Health. The Committee on Exercise and Cardiac Rehabilitation of the American Heart Association endorsed and supported these recommendations. The purpose of the present report is to update and clarify the 1995 recommendations on the types and amounts of physical activity needed by healthy adults to improve and maintain health. Development of this document was by an expert panel of scientists, including physicians, epidemiologists, exercise scientists, and public health specialists. This panel reviewed advances in pertinent physiologic, epidemiologic, and clinical scientific data, including primary research articles and reviews published since the original recommendation was issued in 1995. Issues considered by the panel included new scientific evidence relating physical activity to health, physical activity recommendations by various organizations in the interim, and communications issues. Key points related to updating the physical activity recommendation were outlined and writing groups were formed. A draft manuscript was prepared and circulated for review to the expert panel as well as to outside experts. Comments were integrated into the final recommendation.

Primary Recommendation: To promote and maintain health, all healthy adults aged 18 to 65 yr need moderate-intensity aerobic (endurance) physical activity for a minimum of 30 min on five days each week or vigorous-intensity aerobic physical activity for a minimum of 20 min on three days each week. [I (A)] Combinations of moderate- and vigorous-intensity activity can be performed to meet this recommendation. [IIa (B)] For example, a person can meet the recommendation by walking briskly for 30 min twice during the week and then jogging for 20 min on two other days. Moderate-intensity aerobic activity, which is generally equivalent to a brisk walk and noticeably accelerates the heart rate, can be accumulated toward the 30-min minimum by performing bouts each lasting 10 or more minutes. [I (B)] Vigorous-intensity activity is exemplified by jogging, and causes rapid breathing and a substantial increase in heart rate. In addition, every adult should perform activities that maintain or increase muscular strength and endurance a minimum of two days each week. [IIa (A)] Because of the dose-response relation between physical activity and health, persons who wish to further improve their personal fitness, reduce their risk for chronic diseases and disabilities or prevent unhealthy weight gain may benefit by exceeding the minimum recommended amounts of physical activity. [I (A)]

Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association.

Dose-response issues concerning physical activity and health: an evidence-based symposium.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673600034917.pdf

Effect of sibutramine on weight maintenance after weight loss: a randomised trial

OBJECTIVE: To assess the efficacy and tolerability of orlistat (Xenical®) in producing and maintaining weight loss over a 12-month period. DESIGN: Patients were randomized to double-blind treatment with either orlistat 120 mg or placebo three times daily, in conjunction with a low-energy diet, for 12 months. SETTING: Five centres in the UK. SUBJECTS: 228 obese adult patients with body mass index between 30 and 43 kg/m2 and mean weight 97 kg (range 74–144 kg). INTERVENTIONS: All patients were prescribed a low-energy diet, providing 30% of energy from fat, designed to produce an individually tailored energy deficit of approximately 600 kcal/day, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg or placebo three times daily. MAIN OUTCOME MEASURES: Change in body weight (the primary efficacy parameter), waist circumference and adverse events were reviewed regularly, together with serum lipids, insulin, glucose and plasma levels of fat-soluble vitamins and β carotene. RESULTS: Based on an intent-to-treat analysis, after 1 y of treatment patients receiving orlistat had lost an average of 8.5% of their initial body weight compared with 5.4% for placebo-treated patients; 35% of the orlistat group lost at least 5% of body weight compared with 21% of the placebo group (P<0.05), and 28% and 17%, respectively (P=0.04) lost at least 10% of body weight. Orlistat-treated patients showed significant decreases (P<0.05) in serum levels of total cholesterol, low density lipoprotein cholesterol, and in the low density lipoprotein:high density lipoprotein ratio in comparison with placebo. Both groups had similar adverse-event profiles, except for gastrointestinal events, which were 26% more frequent in the orlistat group but were mostly mild and transient. To maintain normal plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients, compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y, the decrease in vitamin E and β carotene was significantly greater in orlistat-treated patients compared with those receiving placebo (P<0.001). No significant change was found in the mean vitamin E:total cholesterol ratio in either group after 52 weeks. Conclusions: Orlistat, in conjunction with a low-energy diet, produced greater and more frequent significant weight loss than placebo during 1 y of treatment. One-third of orlistat-treated patients achieved clinically relevant weight loss (≥5% initial body weight). There was also an improvement in relevant serum lipid parameters. Fat-soluble vitamin supplements may be required during chronic therapy. Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity.

One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor.

Nerve growth factor (NGF) is trophic to sensory and sympathetic fibers. In animal models, NGF is depleted in diabetic nerves and NGF deprivation produces hypoalgesia. Exogenous NGF can reverse some of the pathological changes in diabetic nerves and NGF excess leads to hyperalgesia. We have quantified sensory and autonomic function in early diabetic polyneuropathy and correlated changes with levels of NGF and neuropeptides in affected skin. We describe an early length-dependent dysfunction of sensory small-diameter fibers, prior to dysfunction of sympathetic fibers, with depletion of skin NGF and the sensory neuropeptide substance P. We describe a significant correlation between NGF depletion and decreased skin axon-reflex vasodilation, mediated by small sensory fibers partly via substance P release. Immunostaining shows depletion of NGF in keratinocytes in diabetic skin. We propose that a decrease in endogenous skin-derived NGF influences the presentation of diabetic polyneuropathy, although metabolic or vascular abnormalities may be the cause of the neuropathy. As loss of nociception and axon-reflex vasodilation contribute to diabetic foot ulceration, early and prolonged NGF treatment at an appropriate dose may provide rational prophylaxis for this condition.

Peter Kopelman

Papers

Obesity as a medical problem

Dose-response issues concerning physical activity and health: an evidence-based symposium.

Effect of sibutramine on weight maintenance after weight loss: a randomised trial

One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor.

The role of endogenous nerve growth factor in human diabetic neuropathy.