Endocrine Abstracts

Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour. An increased understanding of how peripheral energy signals act upon these circuits to regulate food intake is essential for effective treatment of the current obesity crisis.

In response to meal ingestion, several hormones are released from the gastrointestinal tract, which play a role in the regulation of energy homeostasis. Peptide YY (PYY), synthesised by gut-endocrine cells, predominantly as an N-terminally truncated form PYY_3–36, is one such hormone. The first evidence for a role of PYY_3–36 in the regulation of body weight resulted from the findings that peripheral PYY_3–36 administration dose-dependently decreased feeding in rodents. Subsequently, in humans intravenous infusion of PYY_3–36 was found to reduce hunger and decrease 24-h caloric intake in lean, normal-weight and obese subjects. In addition, fasting and postprandial circulating levels of PYY_3–36 were reduced in obese subjects suggesting that PYY-deficiency might contribute to the pathogenesis of obesity. To further understand the physiological role of PYY mice lacking Pyy were generated. These animals were hyperphagic, developed marked obesity but displayed increased sensitivity to exogenous PYY_3–36 which reversed their obese phenotype.

Studies in rodents suggested that the hypothalamus and brainstem were key target sites mediating the anorectic effects of PYY_3–36. To investigate in humans the brain circuits upon which PYY_3–36 acts a double-blind placebo controlled study was undertaken, combining PYY_3–36 infusion with continuous functional magnetic resonance imaging and behavioural measures. PYY_3–36 modulated neural activity within brainstem and hypothalamic regions consistent with rodent studies. However, the greatest effect of PYY_3–36 on brain activity was seen within the left caudolateral orbital frontal cortex (OFC), a polymodal brain region implicated in reward processing. Critically under high PYY_3–36 plasma conditions, mimicking the fed state, changes in neural activity within the OFC predicted subsequent feeding behaviour. In contrast, in low PYY_3–36 conditions, hypothalamic activation predicted subsequent food intake. Thus the presence of postprandial plasma concentrations of PYY_3–36 switched food intake regulation from a homeostatic to a hedonic, corticolimbic area.

The retained responsiveness of obese subjects to the anorectic effects of PYY_3–36 coupled with its newly identified hedonic effects suggest that targeting the PYY system may offer a therapeutic strategy for obesity.