The life of all animals is dominated by alternating feelings of hunger and satiety - the main involuntary motivations for feeding-related behaviour. Gut bacteria depend fully on their host for providing the nutrients necessary for their growth. The intrinsic ability of bacteria to regulate their growth and to maintain their population within the gut suggests that gut bacteria can interfere with molecular pathways controlling energy balance in the host. The current model of appetite control is based mainly on gut-brain signalling and the animal's own needs to maintain energy homeostasis; an alternative model might also involve bacteria-host communications. Several bacterial components and metabolites have been shown to stimulate intestinal satiety pathways; at the same time, their production depends on bacterial growth cycles. This short-term bacterial growth-linked modulation of intestinal satiety can be coupled with long-term regulation of appetite, controlled by the neuropeptidergic circuitry in the hypothalamus. Indeed, several bacterial products are detected in the systemic circulation, which might act directly on hypothalamic neurons. This Review analyses the data relevant to possible involvement of the gut bacteria in the regulation of host appetite and proposes an integrative homeostatic model of appetite control that includes energy needs of both the host and its gut bacteria.

Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3-to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.neuropeptide Y ͉ pancreatic polypeptide ͉ cre-lox ͉ arcuate nucleus N europeptide Y (NPY) in the hypothalamus is known to be a strong stimulus for food intake (1, 2), and induces many neuroendocrine and metabolic changes that favor energy storage. Such changes include decreased thermogenesis in brown adipose tissue, hyperinsulinemia, hypercorticosteronemia, and insulin hyperresponsiveness in white adipose tissue (3, 4). All of these neuroendocrine and metabolic effects of central NPY administration persist even when NPY-induced hyperphagia is prevented by pair-feeding (3, 4), demonstrating that hyperphagia is not the only mechanism by which central NPY increases adiposity.Although numerous other hormones and peptides act within the hypothalamus to regulate energy homeostasis, many exert an important component of their effects via actions on the hypothalamic NPY-ergic system (5-7), demonstrating the pivotal role of NPY in coordinating energy homeostasis. However, it is not clear which of the 5 cloned Y-receptors (Y1, Y2, Y4, Y5, and y6) are responsible for these effects (8).There is increasing evidence that Y2 receptors are involved in energy homeostasis. Over 80% of NPY-containing neurons in the arcuate nucleus (Arc) coexpress Y2 receptor mRNA (9). This presynaptic Y2 receptor has therefore been proposed to regulate the release of NPY (10, 11) and other colocalized neurotransmitters involved ...