Caloric Restriction and Hypothalamic Leptin Gene Therapy Have Differential Effects on Energy Partitioning in Adult Female Rats.

Russell T Turner,Kristina M Fosse,Adam J Branscum,Carmen P Wong,Urszula T Iwaniec

doi:10.3390/ijms22136789

Russell T Turner, Kristina M Fosse + Show 3 more

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https://doi.org/10.3390/ijms22136789

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Abstract

Dieting is a common but often ineffective long-term strategy for preventing weight gain. Similar to humans, adult rats exhibit progressive weight gain. The adipokine leptin regulates appetite and energy expenditure but hyperleptinemia is associated with leptin resistance. Here, we compared the effects of increasing leptin levels in the hypothalamus using gene therapy with conventional caloric restriction on weight gain, food consumption, serum leptin and adiponectin levels, white adipose tissue, marrow adipose tissue, and bone in nine-month-old female Sprague-Dawley rats. Rats (n = 16) were implanted with a cannula in the 3rd ventricle of the hypothalamus and injected with a recombinant adeno-associated virus, encoding the rat gene for leptin (rAAV-Lep), and maintained on standard rat chow for 18 weeks. A second group (n = 15) was calorically-restricted to match the weight of the rAAV-Lep group. Both approaches prevented weight gain, and no differences in bone were detected. However, calorically-restricted rats consumed 15% less food and had lower brown adipose tissue Ucp-1 mRNA expression than rAAV-Lep rats. Additionally, calorically-restricted rats had higher abdominal white adipose tissue mass, higher serum leptin and adiponectin levels, and higher marrow adiposity. Caloric restriction and hypothalamic leptin gene therapy, while equally effective in preventing weight gain, differ in their effects on energy intake, energy expenditure, adipokine levels, and body composition.

Highlights

Normal weight gain during middle age (0.25–0.50 kg/year) is associated with increased risk for several chronic diseases, most notably type II diabetes [1,2]
Whatever the precise mechanism(s) of action, caloric restriction, sufficient to result in a negative energy balance, is a common strategy to lose excess weight and/or mitigate health risks associated with weight gain
We previously evaluated the long-duration effects of increasing hypothalamic leptin levels using gene therapy (rats injected in 3rd ventricle of their hypothalamus with recombinant adenoassociated virus encoding the rat gene for leptin) on energy balance and bone metabolism in 9-month-old female rats [24]

Summary

Introduction

Normal weight gain during middle age (0.25–0.50 kg/year) is associated with increased risk for several chronic diseases, most notably type II diabetes [1,2]. Hypertension, cardiovascular disease and certain cancers are positively associated with weight gain [3]. The underlying mechanisms leading to the energy imbalance responsible for normal weight gain in adults are not well understood, but incremental development of leptin resistance, associated with higher circulating leptin, is thought to be a contributing factor [4]. Decreases in serum leptin levels in overweight individuals result in improved leptin sensitivity [5]. Whatever the precise mechanism(s) of action, caloric restriction, sufficient to result in a negative energy balance, is a common strategy to lose excess weight and/or mitigate health risks associated with weight gain.

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