Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats

doi:10.1016/S0899-9007(99)00088-X

Nutrition

Volume 15, Issues 7–8, July–August 1999, Pages 576-579

https://doi.org/10.1016/S0899-9007(99)00088-X Get rights and content

Abstract

We investigated the effects of leptin on central and/or peripheral feeding-related neuronal networks in Wistar male rats either normal (350–450 g) or Zucker obese (500–800 g). Low doses (1–10 pg) of leptin inhibited glucose-sensitive vagal hepatic afferent discharges and facilitated sympathetic efferent discharges to brown and white adipose tissue. Most (40–75%) neurons in the arcuate nucleus were significantly inhibited by superperfusion with leptin (0.1 nM–10 pM) under in vitro conditions. In anesthetized animals, leptin was applied electrophoretically to single hypothalamic neurons. Both glucose-sensitive neurons (GSNs) and non-GSNs in the feeding center (LHA) were significantly inhibited. Most glucoreceptor neurons in the satiety center (VMH) were significantly excited. Their depolarization was confirmed by activation of Na⁺ and K⁺ channels by 10⁻¹¹ M leptin using the perforate blind patch-clamp method. Although leptin excited GSNs in the parvocellular part of the paraventricular nucleus, the effects of leptin on such neuronal activity were slight or absent in Zucker obese rats. These results suggest that the feeding-suppression effects of leptin are mediated by its effects on signal transduction through both the central and the peripheral nervous systems.

Introduction

In a recent issue of Science1 it was stated that body weight is a lot like the weather: everybody talks about it, but no one seems to be able to do much about it. However, in the past few years researchers have learned a great deal about the physiologic mechanisms that help people keep their energy intake and expenditure in balance. Our knowledge of the part played by the cloned ob-protein (leptin)2 in the regulation of body weight is largely derived from studies performed in rodents and humans.3, 4 Leptin, expressed by the ob gene on white adipocytes, actually plays an important role in the neural (central/peripheral) controls of feeding suppression.5, 6, 7 Leptin receptors are known to be localized in the hypothalamus,8 but its effects on neuronal activity within the feeding-related central (hypothalamic) and/or peripheral nervous systems have not been demonstrated. The purpose of the present study, using normal Wistar and Zucker obese (fa/fa) rats, was to clarify the effects of leptin 1) on neuronal activity in the feeding-related region of the hypothalamus, 2) on vagal hepatic afferents, and 3) on sympathetic efferents to brown and white adipose tissue (BAT/WAT). For this we used anesthetized, brain-slice, and perforate patch-clamp preparations. Some preliminary results have been reported elsewhere.9, 10

Section snippets

Recording of hepatic vagal afferents and BAT/WAT sympathetic efferents

Wistar rats, weighing about 300 g, were used. They were kept in a room at 24°C with illumination for 12 h a day (0700–1900 h). Food, but not water, was removed 12 h before the experiment. Animals were anesthetized by intraperitoneal injection of 1 g/kg urethane, and warmed by a heating pad to maintain the body temperature at about 37°C. After a laparotomy, a catheter was inserted into the portal vein for the administration of this recombinant leptin (PeproTech EC, London, UK, and also donated

Effects of leptin on vagal hepatic afferent neural discharge

It is well known that vagal hepatic afferents perform very important functions in the sending of information from peripheral chemosensors responding to, from metabolic substrate, such as glucose, protein, peptides, and fat, to the feeding-related brain, at least, the hypothalamus. Most of these substances, because of their large molecular weight, have difficulty penetrating the blood-brain barrier and thus do not affect the brain directly. The OB-R (OB receptor), however, the receptor for

Summary

We have revealed the target sites for leptin (as a feedback hormone) using the following evidence:

1.
Leptin inhibited (low dose)/augmented (high dose) hepatic vagal afferent activity.
2.
Leptin enhanced sympathetic efferent neural activity to both WAT and BAT.
3.
Leptin inhibited GSNs in the ACN.
4.
Leptin excited GRNs in the VMH (satiety center).
5.
Leptin inhibited GSNs in the LHA (feeding center).
6.
GSNs in the parvocellular division of the PVN were excited by leptin.
7.
Leptin had little or no effect on the

Conclusion

Our results suggest that the feeding-suppression effects of leptin are mediated by its effects on signal transduction through both the central and peripheral nervous systems.

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Cited by (67)

Obese female Zucker rats (fa/fa) exhibit dendritic retraction in neurons in the ventromedial hypothalamic nucleus
2021, Journal of Chemical Neuroanatomy
Citation Excerpt :
In the present study, we observed that VMH neurons of female OZ rats express dendritic retraction compared to VMH neurons of LE and LZ rats. This phenomenon could be due to the absence of leptin receptor activity because leptin stimulates the activity of different types of neurons in the hypothalamus, including glucose-sensitive parvocellular neurons of the paraventricular nucleus and glucoreceptor neurons of the VMH (Shiraishi et al., 1999). Recent studies indicate that leptin promotes neuronal plasticity in the hippocampus, including events at the synaptic level, neuronal morphological level, glutamate receptor trafficking level, and neuroprotector level, to avoid cellular apoptosis and promote cellular survival (Doherty et al., 2013).
The ventromedial hypothalamic nucleus (VMH) is located in the tuberal region of the hypothalamus and is traditionally considered the satiety center. In obese Zucker rats, which express a mutation in the leptin receptor gene and exhibit obesity from the first weeks of life, the morphology of VMH neurons is unknown. In the present study, we found that the dendritic length of VMH neurons in obese Zucker rats was significantly shorter than that in Long Evans rats. This finding allows us to suggest that obese Zucker rats exhibit both neuronal metabolic alterations related to leptin and a reduction in the flow of information within the neuronal circuits in which the VMH nucleus participates to regulate foraging.
Age-related changes in acute central leptin effects on energy balance are promoted by obesity
2016, Experimental Gerontology
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On the other hand, the activation of the anabolic neuropeptide Y (NPY) and that of the endogenous melanocortin antagonist agouti-related peptide (AgRP) are suppressed (Baskin et al., 1999; Berglund et al., 2012). In the periphery, leptin also acts on different sites of the afferent vagus (Wang et al., 1997; Gaigé et al., 2002; Shiraishi et al., 1999; Buyse et al., 2001), transmitting information to the brainstem and to the nucleus of the solitary tract (NTS) (Buyse et al., 2001; Grill et al., 2002; Székely and Szelényi, 2005). The responsiveness to leptin has been shown to decline (with consequent hyperleptinemia) during the course of age-related weight gain (Scarpace et al., 2000a) and in obesity of other etiologies at any age (Lin et al., 2000; Myers et al., 2012).
Leptin is a key catabolic regulator of food intake (FI) and energy expenditure. Both aging and obesity have been shown to induce leptin-resistance. The present study aimed to analyze age-related changes in the anorexigenic and hypermetabolic responsiveness to acute intracerebroventricular leptin administration in different age-groups of normally fed male Wistar rats (adult and old rats from 3 to 24 months of age, NF3 to NF24, respectively). The expressions of the long form of the leptin receptor (Ob-Rb) and inhibitory SOCS3 genes were also assessed by quantitative RT-PCR in the arcuate nucleus (ARC). The influence of high-fat diet-induced obesity (HF) on the anorexigenic leptin effects were also tested in younger and older middle-aged groups (HF6 and HF12).
Leptin-induced anorexia varied with age: leptin suppressed re-feeding FI (following 48-h fasting) strongly in young adult (NF3), but not in younger or older middle-aged (NF6 or NF12) or in aging (NF18) rats. However, anorexigenic leptin effects reached statistical significance again in old NF24 rats. Leptin-induced hypermetabolism, on the other hand, showed monotonous age-related decline and disappeared by old age. Ob-Rb expression declined until 12 months of age followed by a partial recovery in NF18 and NF24 groups. On the other hand, SOCS3 expression was high in NF6 and NF18 and to some extent in NF24 rats. Age-related alterations of Ob-Rb and SOCS3 expression in the ARC may partly contribute to the explanation of age-related variations in anorexigenic but not hypermetabolic leptin effects. High-fat diet-induced obesity was associated with resistance to leptin-induced anorexia in HF6, similar to that seen in NF6. However, instead of the expected leptin-resistance in HF12, a strong leptin-induced suppression of re-feeding was detected in these obese middle-aged rats.
Our results suggest that acute central effects of leptin on anorexia and hypermetabolism change in disparate ways during aging, implying separate mechanisms (e.g. signal transduction pathways) of different leptin actions. The age-related pattern shown by leptin-induced anorexia may contribute to the explanation of middle-aged obesity, and partly to that of aging anorexia. Our findings concerning obese rats are in accord with previous observations on anorexigenic effects of peripherally administered cholecystokinin: diet-induced obesity appeared to accelerate the development of age-related regulatory alterations. Similarly, our present data also raise the possibility that chronic diet-induced obesity promotes responsiveness to centrally applied leptin at least concerning anorexigenic effects.
Central leptin and tumor necrosis factor-α (TNFα) in diurnal control of blood pressure and hypertension
2016, Journal of Biological Chemistry
Citation Excerpt :
As known, leptin-induced STAT3 activation during the initial phase is mediate through leptin receptor activation-induced JAK2-STAT3 cascade (30). This initial phase of leptin signaling is fast and excites neurons to rapidly induce biological actions (46), some of which might be independent of STAT3 transcriptional program (47–49). In contrast to the short time window of initial leptin signaling, the second phase of leptin-activated STAT3 is moderate but tonic, presumably being involved in certain chronic functions of leptin, such as immune regulation.
Leptin and TNFα can individually work in the brain to affect blood pressure; however, it remains unknown whether these two cytokines might have an interactive role in this process and, if so, how. In this work, we found that leptin stimulation led to TNFα production under both in vitro and in vivo conditions, and diurnal fluctuation of leptin concentrations in the cerebrospinal fluid predicted the circadian changes of TNFα gene expression in the hypothalamus. Signaling analysis showed that leptin stimulation led to a rapid and strong STAT3 activation followed by a second-phase moderate STAT3 activation, which was selectively abolished by anti-inflammatory chemical PS1145 or TNFα antagonist WP9QY. Physiological study in normal mice revealed that diurnal rise of blood pressure was abrogated following central administration of PS1145 or a leptin receptor antagonist. Central TNFα pretreatment was found to potentiate the effect of leptin in elevating blood pressure in normal mice. In pathophysiology, dietary obesity mimicked TNFα pretreatment in promoting leptin-induced blood pressure rise, and this effect was blocked by central treatment with either PS1145 or WP9QY. Hence, central leptin employs TNFα to mediate the diurnal blood pressure elevation in physiology while enhancement of this mechanism can contribute to hypertension development.
The neuroanatomical function of leptin in the hypothalamus
2014, Journal of Chemical Neuroanatomy
The anorexigenic hormone leptin plays an important role in the control of food intake and feeding-related behavior, for an important part through its action in the hypothalamus. The adipose-derived hormone modulates a complex network of several intercommunicating orexigenic and anorexigenic neuropeptides in the hypothalamus to reduce food intake and increase energy expenditure. In this review we present an updated overview of the functional role of leptin in respect to feeding and feeding-related behavior per distinct hypothalamic nuclei. In addition to the arcuate nucleus, which is a major leptin sensitive hub, leptin-responsive neurons in other hypothalamic nuclei, including the, dorsomedial-, ventromedial- and paraventricular nucleus and the lateral hypothalamic area, are direct targets of leptin. However, leptin also modulates hypothalamic neurons in an indirect manner, such as via the melanocortin system. The dissection of the complexity of leptin's action on the networks involved in energy balance is subject of recent and future studies. A full understanding of the role of hypothalamic leptin in the regulation of energy balance requires cell-specific manipulation using of conditional deletion and expression of leptin receptors. In addition, optogenetic and pharmacogenetic tools in combination with other pharmacological (such as the recent discovery of a leptin receptor antagonist) and neuronal tracing techniques to map the circuit, will be helpful to understand the role of leptin receptor expressing neurons. Better understanding of these circuits and the involvement of leptin could provide potential sites for therapeutic interventions in obesity and metabolic diseases characterized by dysregulation of energy balance.
Leptin and aging: Review and questions with particular emphasis on its role in the central regulation of energy balance
2014, Journal of Chemical Neuroanatomy
Leptin is produced mainly in the white adipose tissue and emerged as one of the key catabolic regulators of food intake and energy expenditure. During the course of aging characteristic alterations in body weight and body composition in humans and mammals, i.e. middle-aged obesity and aging anorexia and cachexia, suggest age-related regulatory changes in energy balance in the background. Aging has been associated with increased fat mass, central and peripheral leptin resistance as indicated by its failure to reduce food intake, to increase metabolic rate and thereby to induce weight loss. Leptin resistance is a common feature of aging and obesity (even in the young). The question arises whether aging or fat accumulation plays the primary role in the development of this resistance. The review focuses mainly on mechanisms and development of central leptin resistance. Age-related decline primarily affects the hypermetabolic component of central catabolic leptin actions, while the anorexigenic component is even growing stronger in the late phase of aging. Obesity enhances resistance to leptin at any age, particularly in old rats, calorie-restriction, on the other hand, increases responsiveness to leptin, especially in the oldest age-group. Thus, without obesity, leptin sensitivity appears not to decrease but to increase by old age. Interactions with other substances (e.g. insulin, cholecystokinin, endogenous cannabinoids) and life-style factors (e.g. exercise) in these age-related changes need to be investigated.
Sensory and sympathetic nervous system control of white adipose tissue lipolysis
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Circulating factors are typically invoked to explain bidirectional communication between the CNS and white adipose tissue (WAT). Thus, initiation of lipolysis has been relegated primarily to adrenal medullary secreted catecholamines and the inhibition of lipolysis primarily to pancreatic insulin, whereas signals of body fat levels to the brain have been ascribed to adipokines such as leptin. By contrast, evidence is given for bidirectional communication between brain and WAT occurring via the sympathetic nervous system (SNS) and sensory innervation of this tissue. Using retrograde transneuronal viral tract tracers, the SNS outflow from brain to WAT has been defined. Functionally, sympathetic denervation of WAT blocks lipolysis to a variety of lipolytic stimuli. Using anterograde transneuronal viral tract tracers, the sensory input from WAT to brain has been defined. Functionally, these WAT sensory nerves respond electrophysiologically to increases in WAT SNS drive suggesting a possible neural negative feedback loop to regulate lipolysis.

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Basic Nutritional InvestigationsLeptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats

Abstract

Introduction

Section snippets

Recording of hepatic vagal afferents and BAT/WAT sympathetic efferents

Effects of leptin on vagal hepatic afferent neural discharge

Summary

Conclusion

Cell

Appetite

Brain Res Bull

Peptides

Regulation of body weight

Science

Positional cloning of the mouse obese gene and its human homologue

Nature

The metabolic significance of leptin in humansgender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure

J Clin Endocrinol Metab

Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues

Proc Natl Acad Sci USA

Effects of the obese gene product on body weight regulation in ob/ob mice

Science

Weight-reduction effects of the plasma protein encoded by the obese gene

Science

Recombinant mouse OB proteinevidence for a peripheral signal linking adiposity and central neural networks

Science

Basic Nutritional Investigations
Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats