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 There has been a great deal of discussion and research into obesity in the last couple of years. Western societies spend enormous amounts of money to treat the health consequences of obesity and there are a plethora of diets and some desperate patients even submit to radical surgeries in hopes of gaining control over their body weight. Nature Neuroscience takes an in depth look at obesity. This dedicated issue looks at what sort of tricks are our bodies and brains can play on us. Clearly the mammalian energy balance is controlled by an amazingly complex network of interacting feedback mechanisms that involve the hypothalamus, the brainstem, higher brain centers, and, in the periphery, the stomach, gut, liver, thyroid, and adipose (fat) tissue. We are just beginning to understand these circuits.
In this focus issue of Nature Neuroscience, they highlight several areas where major progress has been made in the past few years. The introduction describes:
In a review of the hypothalamus, authors Lam, Schwartz and Rossetti describe how manipulations of lipid levels or lipid biochemistry in the hypothalamus affect the feeding behavior of mice and baboons. They discuss the evidence that a certain intermediate of fatty acid metabolism, LCFA-CoA, could serve to integrate fat and carbohydrate metabolic signals into an overall measure of energy status.
Roger Cone looks at melanocortin circuits in the hypothalamus and in the brainstem. Mutations in the melanocortin receptor MC4R are the most common genetic cause of inherited obesity. The hypothalamic melanocortin system responds to multiple signals from the periphery, especially hormones and nutrients. Activation of this system has a powerful anorexigenic effect, whereas its inhibition increases food intake and weight. Less is known about the function of the brainstem melanocortin neurons. They seem to pick up a distinct set of peripheral signals and work in concert with the hypothalamic melanocortin system in the regulation of food intake.
A perspective by Tamas Horvath highlights the unusual anatomy and plasticity of the hypothalamic melanocortin system. The synaptic input to several subclasses of modulatory neurons undergoes rapid rearrangement in response to fasting and feeding. Although a causal effect of this plasticity on feeding behavior has not yet been shown, deficiencies in neural plasticity could contribute to disorders of energy homeostasis.
The ob gene was identified over 10 years ago. A mutation of this gene causes obesity in a strain of laboratory mice. Ob codes for the hormone leptin, which is secreted from adipose tissue, signals via receptors in the hypothalamic arcuate nucleus and leads to activation of melanocortin neurons. Injected into mice, leptin causes reduced feeding and weight loss, but it does not have a significant slimming effect in obese patients. Overweight people or rodents have chronically elevated leptin levels because of the increased adipose tissue, but they seem to be resistant to leptin's anorexigenic effects. Heike Münzberg and Martin Myers in their review explain the intricacies of leptin signaling and how overactivation of a simple feedback loop by chronically high leptin levels might contribute to leptin resistance in obesity.
Authors Marzo and Matias review the possible sites and mechanisms whereby endocannabinoids could affect feeding regulation since marijuana, which acts on endocannabinoid receptors, stimulates appetite. The endocannabinoids themselves cause weight gain in animal experiments, and antagonists of the endocannabinoid receptor CB1 cause weight loss. They also summarize the clinical trials of a specific CB1 antagonist that may soon hit the market to treat obesity and metabolic syndrome (a condition that includes overweight, insulin resistance and high blood pressure and that predisposes people to developing diabetes and coronary heart disease).
Eating is a source of pleasure, and has been shown to activate reward circuits that are also involved in the response to drugs of abuse. A commentary by Nora Volkow and Roy Wise explores the parallels between drug addiction and pathological eating, including environmental and neurobiological factors.
The Obesity Research Task Force has been established, which encompasses 15 NIH institutes and several other NIH bodies, led by the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI). The content of this special issue is freely available on the web for three months at http://www.nature.com/neuro/focus/obesity/index.html
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