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Although weight loss can be achieved by any means of energy restriction, current dietary guidelines have not prevented weight regain or population-level increases in obesity and overweight. Many high-carbohydrate, low-fat diets may be counterproductive to weight control because they markedly increase postprandial hyperglycemia and hyperinsulinemia. Many high-carbohydrate foods common to Western diets produce a high glycemic response [high-glycemic-index (GI) foods], promoting postprandial carbohydrate oxidation at the expense of fat oxidation, thus altering fuel partitioning in a way that may be conducive to body fat gain. In contrast, diets based on low-fat foods that produce a low glycemic response (low-GI foods) may enhance weight control because they promote satiety, minimize postprandial insulin secretion, and maintain insulin sensitivity. This hypothesis is supported by several intervention studies in humans in which energy-restricted diets based on low-GI foods produced greater weight loss than did equivalent diets based on high-GI foods. Long-term studies in animal models have also shown that diets based on high-GI starches promote weight gain, visceral adiposity, and higher concentrations of lipogenic enzymes than do isoenergetic, macronutrientcontrolled, low-GI-starch diets. In a study of healthy pregnant women, a high-GI diet was associated with greater weight at term than was a nutrient-balanced, low-GI diet. In a study of diet and complications of type 1 diabetes, the GI of the overall diet was an independent predictor of waist circumference in men. These findings provide the scientific rationale to justify randomized, controlled, multicenter intervention studies comparing the effects of conventional and low-GI diets on weight control.

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Summary Epidemiologic studies indicate that the risks for major age-related debilities including CHD, diabetes, and age-related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age-related retinal lesions that precede AMD (hereafter called AMD-like lesions). We found that consuming a higher GI diet promotes these AMD-like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (p<0.02) and severity (p<0.05) of hallmark age-related retinal lesions such as basal deposits. Consuming higher GI diets was associated with >3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver and brain in the age-matched mice, suggesting diet-induced systemic glycative stress that is etiologic for lesions. Data from live cell and cell free systems show that the ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway (LPS) are involved in the degradation of AGEs. Glycatively-modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE-modification of ubiquitin and ubiquitin conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited indicating that the UPS and LPS interact with one another to degrade AGEs. Together these data explain why AGEs accumulate as glycative stress increases.

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Abstract-Leptin, a circulating hormone produced by adipose tissue, is believed to act on the hypothalamus to increase sympathetic vasomotor activity, in addition to its well-known effects on appetite and energy expenditure. In this study, we determined the cardiovascular effects of direct application of leptin to specific cell groups within the hypothalamus that are known to be activated by circulating leptin. In rats anesthetized with urethane, microinjections of leptin (16 ng in 20 nL solution) were made into the ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and paraventricular nucleus. Compared with vehicle solution, microinjections of leptin into the ventromedial hypothalamic nucleus evoked significant increases in arterial pressure and renal sympathetic nerve activity, but not heart rate. In contrast, microinjections of leptin into the dorsomedial hypothalamic nucleus evoked significant increases in arterial pressure and heart rate but not renal sympathetic nerve activity, whereas microinjections of leptin into the paraventricular nucleus had no significant effect on any of the measured cardiovascular variables. These results indicate that the ventromedial and dorsomedial hypothalamic regions might be important sites at which leptin activation leads to increases in sympathetic vasomotor activity and heart rate, as occurs in obesity-related hypertension. (Hypertension. 2003;42:488-493.)Key Words: hypothalamus Ⅲ sympathetic nervous system Ⅲ arterial pressure Ⅲ heart rate Ⅲ brain Ⅲ hypertension, experimental Ⅲ obesity I t is well established that the circulating hormone leptin, which is produced mainly in white adipose tissue, contributes to body weight homeostasis by reducing appetite and increasing energy expenditure. 1,2 The increase in energy expenditure is due to activation of sympathetic nerves that innervate brown adipose tissue. 3 In addition to these effects, it has also been shown that intravenous administration of leptin increases the activity of sympathetic nerves that innervate the kidneys, hindlimb vasculature, and adrenal glands in anesthetized rats, 3 whereas long-term intravenous or intracarotid infusions of leptin increase arterial pressure and heart rate (HR) in conscious rats. 4 It has therefore been suggested that leptin-induced increases in the activity of sympathetic vasomotor and cardiac nerves might be an important component in obesityrelated hypertension. 5 The leptin-induced increases in sympathetic vasomotor activity, arterial pressure, and HR appear to be mediated via action on the brain, because short-term administration of leptin into the lateral ventricles increases arterial pressure in conscious rats. 6,7 Similarly, long-term administration of leptin into the lateral ventricles of conscious rats also results in a sustained increase in arterial pressure. 8 Circulating leptin has been shown to access the brain via a saturable transport system, 9,10 but the site(s) in the brain at which leptin acts to increase sympathetic vasomotor activity is unknown. Studi...

Background: The optimal diet for pregnancy that is complicated by excessive weight is unknown. Objective: We aimed to examine the effects of a low-glycemic load (low-GL) diet in overweight and obese pregnant women. Design: We randomly assigned 46 overweight or obese pregnant women to receive a low-GL or a low-fat diet. Participants received carbohydrate-rich foods, fats, and snack foods through home delivery or study visits. The primary outcome was birth weight z score. Other endpoints included infant anthropometric measurements, gestational duration, maternal weight gain, and maternal metabolic parameters.Results: There were no significant differences in birth weight z score or other measures of infant adiposity between groups. However, in the low-GL compared with the low-fat group, gestational duration was longer (mean 6 SD: 39.3 6 1.1 compared with 37.9 6 3.1 wk; P = 0.05) and fewer deliveries occurred at 38.0 wk (13% compared with 48%, P = 0.02; with exclusion of planned cesarean deliveries: 5% compared with 53%; P = 0.002). Adjusted head circumference was greater in the low-GL group (35.0 6 0.8 compared with 34.2 6 1.3 cm, P = 0.01). Women in the low-GL group had smaller increases in triglycerides [median (interquartile range): 49 (19, 70) compared with 93 (34, 129) mg/dL; P = 0.03] and total cholesterol [13 (0, 36) compared with 33 (22, 56) mg/dL, P = 0.04] and a greater decrease in C-reactive protein [22.5 (25.5, 20.7) compared with 20.4 (21.4, 1.5) mg/dL, P = 0.007]. Conclusions: A low-GL diet resulted in longer pregnancy duration, greater infant head circumference, and improved maternal cardiovascular risk factors. Large-scale studies are warranted to evaluate whether dietary intervention during pregnancy aimed at lowering GL may be useful in the prevention of prematurity and other adverse maternal and infant outcomes. This trial is registered at clinicaltrials.gov as NCT00364403.Am J Clin Nutr 2010;92:1306-15.

A reduction in dietary fat has been widely advocated for the prevention and treatment of obesity and related complications. However, the efficacy of low-fat diets has been questioned in recent years. One potential adverse effect of reduced dietary fat is a compensatory increase in the consumption of high glycaemic index (GI) carbohydrate, principally refined starchy foods and concentrated sugar. Such foods can be rapidly digested or transformed into glucose, causing a large increase in post-prandial blood glucose and insulin. Short-term feeding studies have generally found an inverse association between GI and satiety. Medium-term clinical trials have found less weight loss on high GI or high glycaemic load diets compared to low GI or low glycaemic load diets. Epidemiological analyses link GI to multiple cardiovascular disease risk factors and to the development of cardiovascular disease and type 2 diabetes. Physiologically orientated studies in humans and animal models provide support for a role of GI in disease prevention and treatment. This review examines the mechanisms underlying the potential benefits of a low GI diet, and whether such diets should be recommended in the clinical setting.