New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

Feeding behavior is critical for survival. In addition to providing all of the body's macronutrients (carbohydrates, lipids, and proteins) and most micronutrients (minerals and vitamins), feeding behavior is a fundamental aspect of energy homeostasis, the process by which body fuel stored in the form of adipose tissue is held constant over long intervals. For this process to occur, the amount of energy consumed must match precisely the amount of energy expended. This review focuses on the molecular signals that modulate food intake while integrating the body's immediate and long-term energy needs.

The adipocyte hormone, leptin (OB protein), is proposed to be an "adiposity signal" that acts in the brain to lower food intake and adiposity. As plasma leptin levels are elevated in most overweight individuals, obesity may be associated with leptin resistance. To investigate the mechanisms underlying brain leptin uptake and to determine whether reduced uptake may contribute to leptin resistance, we measured immunoreactive leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; p = 0.0001). Like levels in plasma, CSF leptin levels were correlated to body mass index (r = 0.43; p = 0.001), demonstrating that plasma leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma leptin ratio) was lower among those in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference). We hypothesize that a saturable mechanism mediates CSF leptin transport, and that reduced efficiency of brain leptin delivery among obese individuals with high plasma leptin levels results in apparent leptin resistance.

Recent evidence suggests a key role for the brain in the control of both body fat content and glucose metabolism. Neuronal systems that regulate energy intake, energy expenditure, and endogenous glucose production sense and respond to input from hormonal and nutrient-related signals that convey information regarding both body energy stores and current energy availability. In response to this input, adaptive changes occur that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in this control system are implicated in the link between obesity and type 2 diabetes.

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The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: the ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ. Diabetes Care 30:162-172, 2007D iabetes is a disease defined by abnormalities of fasting or postprandial glucose and is frequently associated with disorders of the eyes, kidneys, nerves, and circulatory system. Circulatory disorders associated with diabetes include coronary heart disease (CHD), stroke, peripheral arterial disease, cardiomyopathy, and congestive heart failure. Diabetes generally results in early death from cardiovascular diseases (CVDs). In 1999, the American Diabetes Association (ADA) and the American Heart Association (AHA) published a joint statement with the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Foundation International indicating the need for multiorganizational cooperation for prevention of CVD in patients with diabetes (1). The present statement represents a joint response of the ADA and AHA to this challenge.The ADA and AHA each have published guidelines for CVD prevention that overlap with the present statement: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. The present document will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which ADA and AHA recommendations differ.Clear clinical trial evidence published over the past decade suggests that broadbased treatment of dyslipidemia, hypertension, and hypercoagulability (as well as interventional cardiology and cardiovascular surgery during the acute coronary syndrome [2]) can improve the event-free survival rate in people with diabetes who already have clinical CVD. However, a much smaller body of clinical trial data addresses the issue of primary prevention of CVD in patients with diabetes and no known CVD. This is a critical issue because patients with diabetes have twice the risk of incident myocardial infarction and stroke as that of the general population. Furthermore, large numbers of people with diabetes do not survive their first event, and if they do survive, their mortality rate over the subsequent months to years is generally greater than that of the general population. As many as 80% of patients with type 2 diabetes will develop and possibly die of macrovascular disease. This represents a great societal cost, with major loss of life expectancy and quality of life (3,4). Although the i...

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