Obesity is associated with resistance of skeletal muscle to insulin-mediated glucose uptake, as well as resistance of different organs and tissues to other metabolic and vascular actions of insulin. In addition, the body is exquisitely sensitive to nutrient imbalance, with energy excess or a high fat diet rapidly increasing insulin resistance even before noticeable changes occur in fat mass. There is a growing acceptance of the fact that, as well as acting as a storage site for surplus energy, adipose tissue is an important source of signals relevant to, inter alia, energy homeostasis, fertility and bone turnover. It has also been widely recognised that obesity is a state of low-grade inflammation, with adipose tissue generating substantial quantities of pro-inflammatory molecules. At a cellular level, the understanding of the signaling pathways responsible for such alterations has been intensively investigated. What is less clear, however, is how alterations of physiology, and of signaling, within one cell or one tissue are communicated to other parts of the body. The concepts of cell signals being disseminated systemically through a circulating 'endocrine' signal have been complemented by the view that local signaling may similarly occur through 'autocrine' or 'paracrine' mechanisms. Yet while much elegant work has focussed on the alterations in signaling which are found in obesity or energy excess, there has been less attention paid to ways in which such signals may propagate to remote organs. This review of the integrative physiology of obesity critically appraises the data and outlines a series of hypotheses as to how inter-organ cross-talk takes place. The hypotheses presented include the 'fatty acid hypothesis', the 'portal hypothesis', the 'endocrine hypothesis', the 'inflammatory hypothesis', the 'overflow hypothesis', a novel 'vasocrine' hypothesis, and a 'neural hypothesis' - and the strengths and weaknesses of each hypothesis are discussed.