Leptin production in human adipose tissue.

Following the initial confirmation of the existence of leptin in humans by Friedman and his colleagues (Zhang et al. I994), many publications rapidly appeared concerning all aspects of its regulation and action. However, only a small proportion of these have addressed the in vivo physiology of leptin in man. It is apparent that the main determinant of leptin concentrations in both animals and human subjects is whole-body fat mass (Lonnqvist et al. 1995; Maffei et al. 1995; Considine et al. 1996; Bray & York, 1997). The major target for leptin action in rodents is the hypothalamus (Campfield et al. 1995, 1996; Stephens et al. 1995; Tartaglia et al. 1995). The effects of leptin on the human hypothalamus may be inferred from on-going human clinical trials in which leptin is being administered therapeutically to obese subjects, who have either high leptin concentrations (Amgen Inc., Thousand Oaks, CA, USA), or the very rare leptin deficiency states (Montague et al. 1997~). However, many questions remain unanswered regarding the place of leptin in human energy regulation. These include the manner in which different endocrine and paracrine regulators interact in both the acute and longer-term regulation of leptin production, and the physiological time courses of both the regulation and actions of leptin. Furthermore, the extent to which leptin influences energy balance through actions at peripheral target organs requires further clarification (see Cawthome etal. 1998). In the present paper we have focused on the question of the short-term regulation of leptin production in human subjects. Rather than try to cover comprehensively areas of the leptin field that are discussed in detail elsewhere in the present symposium, or in other reviews (Trayhum, 1996; Bray & York, 1997; Halaas & Friedman, 1997), we will seek to focus on: (1) the effect of obesity on leptin production by human adipose tissue; (2) the effect of feeding on leptin production by human adipose tissue; (3) the periodicity of leptin production in human subjects; (4) the effects of sympathomimetic agents on circulating leptin concentrations; (5) the effect of thyroid status on circulating leptin concentrations. Finally, we discuss the possibility that the modulation of the shortterm regulation of leptin may offer therapeutic opportunities in the management of obesity. Before turning to these questions, however, we will first discuss some of the methodological issues concerning the study of human adipose tissue in vivo. Methods for studying human adipose tissue