Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg͞kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ؎ 2.5 (mean ؎ SEM) at baseline to 26.9 ؎ 2.1 kg͞m 2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.T he increasing rates of obesity and consequent morbidity represent a major epidemic worldwide and threaten to bankrupt health care systems (1-3). While prevention is of great importance, it is medically relevant to identify biological pathways with the potential to treat obesity and related disorders, particularly in adults with fully established obesity and comorbid conditions, such as type 2 diabetes mellitus. Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4). Mutations in the leptin pathway can be a cause of human obesity (5-7). In children with complete leptin deficiency and who are still in the process of gaining weight and developing obesity, leptin replacement therapy can lead to substantial weight reduction (8,9).It is still unknown whether the leptin pathway is relevant to the treatment of established morbid obesity and its endocrine and metabolic consequences in adults. We addressed this question by treating three homozygous leptin-deficient adults with morbid obesity. Morbid obesity had been fully established for two to four decades in those patients, and they had been at a stable (but very high) weight for Ͼ10 years. They were hypogonadal, and one of them had type 2 diabetes mellitus. We report here the results of the first 18 months of replacement therapy with recombinant human leptin, showing that leptin is highly effective in dramatically reducing...

To decide whether tubuloglomerular feedback (TGF) can account for renal autoregulation, we tested predictions of a TGF simulation. Broad-band and single-frequency perturbations were applied to arterial pressure; arterial blood pressure, renal blood flow and proximal tubule pressure were measured. Data were analyzed by linear systems analysis. Broad-band forcings of arterial pressure were also applied to the model to compare experimental results with simulations. With arterial pressure as the input and tubular pressure, renal blood flow, or renal vascular resistance as outputs, the model correctly predicted gain and phase only in the low-frequency range. Experimental results revealed a second component of vascular control active at 100-150 mHz that was not predicted by the simulation. Forcings at single frequencies showed that the system behaves linearly except in the band of 33-50 mHz in which, in addition, there are autonomous oscillations in TGF. Higher amplitude forcings in this band were attenuated by autoregulatory mechanisms, but low-amplitude forcings entrained the autonomous oscillations and provoked amplified oscillations in blood flow, showing an effect of TGF on whole kidney blood flow. We conclude that two components can be detected in the dynamic regulation of renal blood flow, i.e., a slow component that represents TGF and a faster component that most likely represents an intrinsic vascular myogenic mechanism.

We compared conducted vasomotor responses in juxtamedullary microcirculation in normotensive Sprague-Dawley (SD) and spontaneously hypertensive rats (SHR). The goals of the study were as follows: 1) decide whether internephron coupling is facilitated by conducted vasomotor responses; 2) determine whether the magnitude of induced vasoconstriction decreases with increasing distance from the stimulation site; and 3) determine whether the response is stronger in SHR than in SD rats. Microapplication of KCl to the distal afferent arteriole caused local vasoconstriction that was rapidly conducted (speed > 3.0 mm/s) into the cortical radial artery and neighboring afferent arterioles in SD and SHR. The strength of the response was significantly greater (approximately 40%, P < 0.025) in SHR than SD, and the magnitude decreased monotonically with increasing distance from the stimulation site in both strains. Mechanical length constants were similar in SD and SHR (approximately 325 microm), indicating that the signal responsible for the effect decays at the same rate in both strains. We conclude that internephron coupling strength is significantly greater in SHR and that internephron coupling is due to vascular events conducted along the preglomerular vasculature.