Central Nervous System Mechanisms Linking the Consumption of Palatable High-Fat Diets to the Defense of Greater Adiposity

Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Cell metabolism (Impact Factor: 17.57). 02/2012; 15(2):137-49. DOI: 10.1016/j.cmet.2011.12.013
Source: PubMed


The central nervous system (CNS) plays key role in the homeostatic regulation of body weight. Satiation and adiposity signals, providing acute and chronic information about available fuel, are produced in the periphery and act in the brain to influence energy intake and expenditure, resulting in the maintenance of stable adiposity. Diet-induced obesity (DIO) does not result from a failure of these central homeostatic circuits. Rather, the threshold for defended adiposity is increased in environments providing ubiquitous access to palatable, high-fat foods, making it difficult to achieve and maintain weight loss. Consequently, mechanisms by which nutritional environments interact with central homeostatic circuits to influence the threshold for defended adiposity represent critical targets for therapeutic intervention.

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    • "Please cite this article in press as: la Fleur SE, Serlie MJ, The interaction between nutrition and the brain and its consequences for body weight gain and metabolism; studies in rodents and men, Best Practice & Research Clinical Endocrinology & Metabolism (2014), result in obesity with increases in both insulin and leptin levels, which in turn can inhibit reward via their receptors on dopaminergic neurons in the VTA [33e36]. However, in obesity, central leptin and insulin resistance occur [3] [4] and thus the peripheral hormonal signals might not counteract the effects of sugar and fat on the brains reward circuitry thus contributing to disrupted feeding behavior. In summary, regular consumption of high caloric food directly affects the brain circuitries involved in reward and homeostatic control of food intake, thereby increasing the risk for a food addiction like phenotype (Fig. 1). "
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    ABSTRACT: Aberrant feeding behavior can lead to obesity and obesity-related medical consequences, such as insulin resistance and diabetes. Although alterations in glucose metabolism (i.e. insulin resistance), in the presence of excessive fat tissue are often explained by the consequences of dysfunctional adipose tissue, evidence is emerging that also altered brain functions might be an important determinant of insulin resistance. In this review, we provide an overview of how feeding behavior and obesity interact with brain circuitry and how these interactions affect glucose metabolism. Because brain circuitries involved in food intake have been shown to partly control glucose metabolism as well, targeting these circuitries in obese subjects might not only affect food intake and body weight but also glucose metabolism.
    Best Practice & Research: Clinical Endocrinology & Metabolism 10/2014; DOI:10.1016/j.beem.2014.06.001 · 4.60 Impact Factor
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    • "Thus, understanding the biological mechanisms regulating metabolic flexibility might lead to better therapeutic strategies tackling metabolic disorders. HFD consumption plays a significant role in the development of insulin and leptin resistance in the central nervous system (CNS) [2]. In addition, recent studies have demonstrated that nutrients are not only a source of calories, but also work as intracellular signals capable of modifying the activity of specific molecular cascades [3] [4]. "
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    ABSTRACT: Metabolic flexibility allows rapid adaptation to dietary change, however little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.Figure optionsDownload full-size imageDownload as PowerPoint slide
    Molecular Metabolism 08/2014; 3(7). DOI:10.1016/j.molmet.2014.07.004
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    • "However, weight loss is strongly countered by physiological compensatory responses that often defeat attempts to stay on a diet regimen and maintain weight loss [2], [3]. It has been proposed that obesity is not a state where energy homeostasis is dysregulated, but where the defended body weight level, or set point, is shifted upwards [4]. This is a major obstacle that needs to be overcome if obesity and overeating are to be contained. "
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    ABSTRACT: Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.
    PLoS ONE 05/2014; 9(5):e93691. DOI:10.1371/journal.pone.0093691 · 3.23 Impact Factor
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