Hypothalamic Fatty Acid Sensing in the Normal and Disease States

Despite the undeniable influence of genetic and environmental factors, obesity is ultimately a resultant of, and perpetuated by, a disruption in energy homeostasis, whereby energy (food) intake exceeds energy expenditure. Normally, there is a series of concerted physiological and biochemical checks and balances initiated to handle acute, day-to-day fluctuations in energy balance: for example, an elevation in adiposity resulting from increased energy intake leads to counter-regulation via an increase in adipose-derived hormones, such as lesptin (Friedman, 2003), and an increase in energy expenditure (López et al., 2007). Conversely, the fasting state shifts the energy balance such that energy stores are maintained while an increased propensity for food intake results (Lelliott and Vidal-Puig, 2004). As a result of these feedback signals that relay changes in energy status, the caloric storage/body weight is generally stable for most humans over long periods of time despite the wide variations in day-to-day food intake that occur. These above homeostatic responses are poised to handle subthreshold fluctuations in food intake, but clearly, chronic hyper-caloric excess combined with reduced energy mobilization (i.e., exercise) limits their effectiveness (López et al., 2007), and leads to increased adiposity. In addition, this physiological cross-regulation also provides a reason for the inherent difficulty in losing large amounts of weight and sustaining that weight loss, as massive weight loss is capable of triggering rebound hunger (Friedman, 2003). Further impacting the effectiveness of the energy balance mechanism is the influence of the inherent sensory circuitry that mediates the pleasure and reward on feeding (Flier, 2004). Thus, identifying the nature of the satiety and hunger signals generated in the body that are involved in the regulation of feeding behavior has historically been a necessary preoccupation in obesity research. By the mid-twentieth century, the glucostatic (Mayer, 1953) and lipostatic (Kennedy, 1953) hypotheses, which proposed that circulating nutrients (glucose and lipids, respectively) generated in amounts proportional to peripheral storage depots serve as signals to the brain in order to mediate alterations in energy intake and expenditure, were in place. As a result, research then shifted to focus on the primary energy storage sites in the periphery, including the adipose tissue, skeletal muscle, and the liver, and their potential ability to sense energy and mediate the control of energy intake. The liver, given that it is exposed to the postabsorption nutrient flow (Langhans, 1996) and that hepatocytes are essentially able to metabolize all fuels (Seifter and Englard, 1988), was a natural target that in particular was quite convincingly demonstrated as a possible mediator of the hunger/satiety signal (Langhans, 1996). However, the hypothalamus in particular has long been championed as a key mediator of whole body energy homeostasis. Presently, it is generally accepted that it is involved in the day-to-day regulation of a number of factors including body temperature, blood pressure, thirst, and hunger, and is a vital structure for the integration of the nervous and endocrine systems. The first demonstrations of the hypothalamus serving as a satiety centre were conducted several decades ago, wherein hyperphagia and obesity resulted after the ventromedial nucleus of the hypothalamus was subjected to bilateral lesions (Hetherington and Ranson, 1942). Furthermore, the observed hyperphagia following the administration of the classical 2-deoxyglucose (2-DG) antime-tabolite into the third ventricle of the brain (Miselis and Epstein, 1975) demonstrated a central fuel-sensing component to the regulation of energy homeostasis. Numerous landmark studies—the vast majority of which were conducted in the past decade—have demonstrated that the latter possibility holds much promise. The central nervous system (CNS) has been shown to sense hormones and nutrients in order to regulate not only food intake (Cota et al., 2006; Lam et al., 2008; Luheshi et al., 1999; Morton et al., 2006; Turton et al., 1996; Wolfgang and Lane, 2006) but also glucose homeostasis (Bence et al., 2006; Coppari et al., 2005; Gelling et al., 2006; Inoue et al., 2006; Kievit et al., 2006; Lam et al., 2005a,b,c; Obici et al., 2002a,b 2003). Of particular interest and relevance, changes in hypothalamic fatty acid levels and metabolism have been shown to regulate both food intake (Loftus et al., 2000) and glucose homeostasis (Obici et al., 2002a, 2003). As obesity and diabetes are characterized by hyperphagia and hyperglycemia, the characterization of defects in the hormone- and nutrient-sensing pathways in the hypothalamus that regulate energy and glucose homeostasis will shed light on the central component that initiates and perpetuates these metabolic diseases.