Physiological response to long-term peripheral and central leptin infusion in lean and obese mice

Abstract

Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue. High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin insensitivity. This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among lean and three obese strains of mice: diet-induced obese AKR͞J, New Zealand Obese (NZO), and A y . Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels. Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng͞hr or greater resulted in complete depletion of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion. Direct measurement of energy balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean mice. NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. A y mice did not respond to subcutaneous leptin and were 1͞100 as sensitive to i.c.v. leptin. The decreased response to leptin in diet-induced obese, NZO, and A y mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the result of decreased transport of leptin into the cerebrospinal f luid, whereas in A y mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.

Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

“…A decrease in the ratio CSF-to-serum leptin concentrations suggested that a failure at the level of the transport from blood to CSF could be the cause of leptin resistance in obese humans [8]. This also has been reported in another experimental model with leptin resistance such as the New Zealand obese mice [10]. These animals respond to i.c.v.…”

“…Leptin transport across the bloodbrain barrier and/or the blood-cerebrospinal fluid barrier, any of the steps of the hormonal signal transduction cascade in the hypothalamus or even steps beyond the leptin-sensitive neurons are possible targets to be altered in leptin resistance states such as obesity and ageing. Alteration of leptin transport across the blood-brain barrier has been proposed to occur in obese humans [8,9], in New Zealand obese mice [10] and in diet-induced obese mice [11]. An impairment in the leptin signal transduction cascade has been shown in the old Fisher 344XBN rat [12,13].…”

Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet

“…[34][35][36] Although leptin resistance was reported in obesity, 37 reduced Arc NPY content in our mice at 10 weeks may represent a possible response to the hyperleptinemia. The decreased NPY concentrations in the AH and PH may reflect a decrease in NPY release from the Arc.…”

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

“…Most obese humans and rodents have elevated serum leptin and impaired physiological responses to exogenously administered leptin, and are hence considered leptin-resistant [1][2][3][4][5]. In contrast, in lean rodents leptin evokes potent anorectic and thermogenic responses and produces marked lipopenia and weight reduction [6][7][8].…”