The Effects of Leptin Administration in Non‐obese Human Subjects

Abstract

MACKINTOSH, RONALD M. AND JULES HIRSCH.The effects of leptin administration in non-obese human subjects. Obes Res. 2001;9:462-469. Objective: Body fatness is partly under hypothalamic control with effector limbs that include the endocrine system and the autonomic nervous system (ANS). In previous studies of both obese and never-obese subjects, we have shown that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the effect of leptin, independent of weight change, on the ANS. Research Methods and Procedures:Normal weight males (ages 20 -40 years) were fed a solid food diet, measured carefully to maintain body weight, for 3 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, 22-day, placebo/drug/placebo design, six subjects received leptin 0.3 mg/kilogram subcutaneously for 6 days. ANS measures of amount of parasympathetic control and sympathetic control of heart period (interbeat interval) were made by sequential pharmacological blockade with intravenous atropine and esmolol. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were also measured as well as resting metabolic rate. Results: Sufficient food intake maintained constant body weight in all subjects. There was no evidence that leptin administration led to changes in energy metabolism sufficient to require additional food intake or to alter resting metabolic rate. Likewise, leptin administration did not alter autonomic activity. Parasympathetic control and sympathetic control, as well as the urinary catecholamines, were not significantly affected by leptin administration. Glucose and insulin levels were increased by food intake as expected, but leptin had no affect on these levels before or after food intake. Discussion: ANS responses to changes in energy metabolism found when food intake and body weight are altered were not found in these never-obese subjects given leptin for 6 days. Although exogenous leptin administration has profound effects on food intake and energy metabolism in animals genetically deprived of leptin, we found it to have no demonstrable effect on energy metabolism in neverobese humans. The effects of longer periods of administration to obese individuals and to those who have lost weight demand additional investigation.

Ghrelin Stimulates Appetite, Imagination of Food, GH, ACTH, and Cortisol, but does not Affect Leptin in Normal Controls

“…Similarly, nocturnal leptin concentrations remained unchanged after repetitive administration of 40 Â 50 mg ghrelin, a dose which did not affect appetite (Weikel et al, 2003), and after the synthetic GHS, hexarelin in young normal men (Frieboes et al, 2004). Furthermore, injection of leptin into nonobese humans had no effects on the cardiovascular or autonomic nervous systems and no evident effects on weight control (Mackintosh and Hirsch, 2001). Possible long-term effects of ghrelin on leptin in humans should be investigated in future studies.…”

Increased leptin expression selectively in the hypothalamus suppresses inflammatory markers CRP and IL-6 in leptin-deficient diabetic obese mice

“…The fourth new finding of this investigation relates to the role of hyperleptinemia in causing chronic low-grade inflammation and secretions of pro-inflammatory CVD markers [21,28,34,42]. Although a positive relationship between hyperleptinemia and high levels of IL-6 and CRP have been observed in obese patients, experimental evidence that peripheral actions of leptin on targets in the periphery engenders these relationships is scarce.…”

“…A similar outcome of a single central injection of rAAV-lep persisting for longer periods was observed in wt rodents and ob/ ob mice [6][7][8][9]14,32,46,47]. The efficacy of the stable leptin expression, specifically in the hypothalamus in minute amounts, to curb accumulation of fat for the lifetime of rodents is important because excessive long-term secretion of several adipokines contributes to a state of chronic, systemic and local vascular inflammation as the volume of adipose tissue, especially visceral adipose tissue, expands [19,21,33,34,36,38,42,45]. The co-morbidities of obesity, in particular CVD and diabetes, are hypothesized to be due, in part, to persistence of chronic lowgrade, subclinical inflammation.…”

“…Positive correlations between plasma leptin and CRP concentrations with increasing adiposity have been reported. Administration of leptin to humans was also shown to increase blood CRP levels [21,34]. The evidence that leptin can stimulate the production of CRP by cultured human hepatocytes implied that leptin may play a role in the physiological regulation of CRP [11].…”

The evolution of body fatness: trading off disease and predation risk

“…However, apart from in a few unusual cases, leptin production in individuals with obesity is completely normal and they have very high levels of circulating leptin (Considine et al, 1996;Maffei et al, 1995;Adami et al, 1998;Campostano et al, 1998). Nevertheless, injecting leptin into mice reduced their body fatness Pellymounter et al, 1995, but see Mackintosh andHirsch 2001;Faouzi et al, 2007). This was followed up by several trials where people with obesity were given exogenous leptin; however, adding leptin to a high existing level had very little impact (Heymsfield et al, 1999).…”