Over 60% of U.S. adults are overweight (BMI >25 kg/m2) or obese (BMI > 30 kg/m2) and at risk for adiposity-related morbidities such as diabetes mellitus and hyperlipidemia. The intractable nature of obesity is reflected in the 75%–95% recidivism rate to obesity among the formerly obese. Studies have shown that maintenance of a reduced body weight, with resultant declines in circulating concentrations of leptin, is accompanied by decreased energy expenditure and increased hunger/food intake that act coordinately to favor the regain of lost weight in humans and rodents. Brain regions known to be involved in the regulation of energy intake have been identified largely through physical and, more recently, molecular lesioning of relevant CNS pathways . For example, the hypothalamus has afferent and efferent connections to the brainstem, midbrain, amygdala, hippocampus, and cortex, which, if selectively lesioned or stimulated, result in predictable alterations in feeding behavior. Increased hunger and food intake during attempts to maintain weight loss are a critical problem in clinical management of obesity. As a result, a study published in the Journal Clinical Investigation (2008;118:2583-2591 was performed to determine whether reduced body weight maintenance is accompanied by leptin-sensitive changes in neural activity in brain regions affecting regulatory and hedonic aspects of energy homeostasis. For the study, brain region–specific neural activity elicited by food-related visual cues was examined using functional MRI in 6 inpatient obese subjects. Subjects were assessed at their usual weight and, following stabilization at a 10% reduced body weight, while receiving either twice daily subcutaneous injections of leptin or placebo. Following weight loss, there were predictable changes in neural activity, many of which were reversed by leptin, in brain areas known to be involved in the regulatory, emotional, and cognitive control of food intake. Specifically, following weight loss there were leptin-reversible increases in neural activity in response to visual food cues in the brainstem, culmen, parahippocampal gyrus, inferior and middle frontal gyri, middle temporal gyrus, and lingual gyrus. There were also leptin-reversible decreases in activity in response to food cues in the hypothalamus, cingulate gyrus, and middle frontal gyrus. These data are consistent with a model of the weight-reduced state as one of relative leptin deficiency.

Diabetic individuals have a significantly higher risk of developing Alzheimer’s disease (AD) but the 1) ___ connection between the two remains unexplained. Researchers at the Salk Institute for Biological Studies identified the probable molecular basis for the diabetes — AD interaction. Their research showed that blood vessels in the brain of young diabetic mice are damaged by the interaction of 2) ___ blood glucose levels characteristic of diabetes and low levels of beta amyloid, a peptide that clumps to form the senile plaques that riddle the brains of AD patients. Although the damage took place long before the first 3) ___ appeared, the mice suffered from significant memory loss and an increase in inflammation in the brain. Although the toxic beta amyloid peptide was first isolated from the brain blood vessels of AD patients, the contribution of pathological changes in brain 4) ___ tissue to the disease has not been well studied. Data clearly describe a 5) ___ mechanism to explain the epidemiology, and identify targets for drug development. AD and diabetes are two diseases that are increasing at an alarming rate within the U.S. population. Alzheimer’s affects one in 10 Americans over 65 years of age and nearly 50% of those over 85 years old. Similarly, 7% or approximately 20 million Americans have diabetes, with the vast majority of these individuals being over 60. Recent 6) ___ studies have shown that diabetic patients have a 30 to 65% higher risk of developing AD compared to non-diabetic individuals. The increased risk applies to both type 1 and type 2 diabetes, which share 7) ___ as a common pathogenic factor. Many studies have focused on altered insulin signaling in the brain as a possible mechanism for the association between AD and diabetes but researchers paid much less attention to the direct affects of increased blood 8) ___ levels on brain function and the pathogenesis of AD. To get at the bottom of the question why diabetes predisposes people to AD as they age, diabetes was induced in young mice, whose genetic background predisposes them to acquire the symptoms of AD with old age. These mice suffered damage to blood 9) ___ well before any overt signs of AD such as nerve cell death or the acquisition of amyloid deposits, the hallmark of the disease, could be detected in their brains. Further experiments revealed that the vascular damage was due to the overproduction of free radicals, resulting in oxidative damage to the cells lining the 10) ___ blood vessels. While all people have a low level of amyloid circulating in their blood, in diabetics there may be a synergistic toxicity between the amyloid and high level of blood glucose that is leading to the problems with proper blood vessel formation.

ANSWERS: 1) molecular; 2) elevated; 3) plaques; 4) vascular; 5) biochemical; 6) epidemiological; 7) hyperglycemia; 8) glucose; 9) vessels; 10) brain’s