Leptin Does Not Directly Affect CNS Serotonin Neurons to Influence Appetite (original) (raw)
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Molecular Metabolism, 2014
Objective: Leptin responsive neurons play an important role in energy homeostasis, controlling specific autonomic, behavioral, and neuroendocrine functions. We have previously identified a population of leptin receptor (LepRb) expressing neurons within the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHA) which are related to neuronal circuits that control brown adipose tissue (BAT) thermogenesis. Intra-DMH leptin injections also activate sympathetic outflow to BAT, but whether such effects are mediated directly via DMH/DHA LepRb neurons and whether this is physiologically relevant for whole body energy expenditure and body weight regulation has yet to be determined. Methods: We used pharmacosynthetic receptors (DREADDs) to selectively activate DMH/DHA LepRb neurons. We further deleted LepRb with virally driven cre-recombinase from DMH/DHA neurons and determined the physiological importance of DMH/DHA LepRb neurons in whole body energy homeostasis. Results: Neuronal activation of DMH/DHA LepRb neurons with DREADDs promoted BAT thermogenesis and locomotor activity, which robustly induced energy expenditure (p < 0.001) and decreases body weight (p < 0.001). Similarly, intra-DMH/DHA leptin injections normalized hypothermia and attenuated body weight gain in leptin-deficient ob/ob mice. Conversely, ablation of LepRb from DMH/DHA neurons remarkably drives weight gain (p < 0.001) by reducing energy expenditure (p < 0.001) and locomotor activity (p < 0.001). The observed changes in body weight were largely independent of food intake. Conclusion: Taken together, our data highlight that DMH/DHA LepRb neurons are sufficient and necessary to regulate energy expenditure and body weight.
Endocrinology, 2008
Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glu...
Regulation of appetite: role of leptin in signalling systems for drive and satiety
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity, 2001
The healthy regulation of appetite involves a balance between excitatory (drive) and inhibitory (satiety) processes. For many years research has concentrated on the identification of signalling systems that mediate satiety to the relative exclusion of drive-inducing biological events. However, the so-called long-term regulation of body weight has recently been given substance by the identification of a chemical signal believed to link the brain with adipose tissue stores. This signal, leptin, is in position to modulate the expression of a drive to eat. Studies on the relationship between leptin and perceived hunger, and on the eating behaviour of leptin-deficient individuals, are consistent with the intervention of leptin in a drive system. The contrast between the roles of leptin and serotonin in appetite regulation reflects the difference between drive-signalling and satiety signalling processes. It is proposed that leptin modulates the drive signals arising from the metabolic dem...
Endocrinology, 2012
The action of peripherally released leptin at long-form leptin receptors (LepRb) within the brain represents a fundamental axis in the regulation of energy homeostasis and body weight. Efforts to delineate the neuronal mediators of leptin action have recently focused on extrahypothalamic populations and have revealed that leptin action within the nucleus of the solitary tract (NTS) is critical for normal appetite and body weight regulation. To elucidate the neuronal circuits that mediate leptin action within the NTS, we employed multiple transgenic reporter lines to characterize the neurochemical identity of LepRb-expressing NTS neurons. LepRb expression was not detected in energy balance-associated NTS neurons that express cocaine- and amphetamine-regulated transcript, brain-derived neurotrophic factor, neuropeptide Y, nesfatin, catecholamines, γ-aminobutyric acid, prolactin-releasing peptide, or nitric oxide synthase. The population of LepRb-expressing NTS neurons was comprised of...
Endocrinology, 2016
Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate leptin responsive neurons are less defined. In the current study, we generated mice with widespread inactivation of the long leptin receptor isoform in the central nervous system via Synapsin promoter-driven Cre (Leprflox/flox Syn-cre mice). Within the hypothalamus, leptin signaling was disrupted in the lateral hypothalamic area (LHA) and ventral premammillary nucleus (PMV) but remained intact in the arcuate hypothalamic nucleus and ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and nucleus of the tractus solitarius. To investigate the role of LHA/PMV neuronal leptin signaling, we examined glucose and energy homeostasis in Leprflox/flox Syn-cre mice and Leprflox/flox littermates under basal and diet-induced obese conditions and tested the role of LHA/PMV neurons in lept...
Cell Metabolism, 2009
The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system. Cell Metabolism LHA LepRb Neurons Modulate Dopamine and Feeding 90 Cell Metabolism 10, 89-98, August 6,
Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area
Neuron, 1999
cortical mantle (Bittencourt et al., 1992). Recent studies have also identified the orexins (ORX) (Sakurai et al., 1998) or hypocretins (de Lecea et al., 1998) as neuropeptides whose cell bodies are found in the LHA and perifornical area of the rat, mouse, and human brain (Broberger ; Elias et al., 1998a; Peyron et al., 1998). Beth Israel Deaconess Medical Center and Similar to MCH, the entire neuraxis receives ORX in-Program in Neuroscience nervation (Peyron et al., 1998; Date et al., 1999; van Harvard Medical School den Pol, 1999). Intracerebroventricular injections of both † Department of Medicine and MCH and ORX increase food intake, and mRNA levels Division of Endocrinology of both peptides are elevated during fasting (Qu et al., Beth Israel Deaconess Medical Center and 1996; Sakurai et al., 1998). Finally, targeted deletion of Harvard Medical School the MCH gene decreases food intake, body weight, and Boston, Massachusetts 02215 adipose tissue mass similar to rats with LHA lesions (Shimada et al., 1998). These observations suggest that LHA neurons play an important role in integrating and influenc-Summary ing the complex physiology underlying feeding behavior. Another brain region that plays an integral role in regu-Recent studies have reinforced the view that the lateral lating body weight and food intake is the arcuate nucleus hypothalamic area (LHA) regulates food intake and of the hypothalamus (Arc). Specifically, the Arc contains body weight. We identified leptin-sensitive neurons in neurons expressing the orexigenic peptide, neuropepthe arcuate nucleus of the hypothalamus (Arc) that tide Y (NPY) (see Woods et al., 1998). NPY neurons innervate the LHA using retrograde tracing with leptin within the Arc coexpress leptin receptor mRNA (Mercer administration. We found that retrogradely labeled et al., 1996a). Leptin deficiency in the fasting state or in cells in the Arc contained neuropeptide Y (NPY) mRNA ob/ob and db/db mice markedly elevates NPY mRNA. or proopiomelanocortin (POMC) mRNA. Following lep-Leptin administration decreases the Arc NPY mRNA levtin administration, NPY cells in the Arc did not express els in ob/ob mice and fasted rodents (Stephens et al., Fos but expressed suppressor of cytokine signaling-3 1995; Ahima et al., 1996; Schwartz et al., 1996). (SOCS-3) mRNA. In contrast, leptin induced both Fos Melanocortin peptides synthesized in the Arc are also and SOCS-3 expression in POMC neurons, many of important regulators of body weight and food intake. which also innervated the LHA. These findings suggest The proopiomelanocortin (POMC) gene product ␣-melathat leptin directly and differentially engages NPY and nocyte-stimulating hormone (␣-MSH) inhibits feeding POMC neurons that project to the LHA, linking circu-(even in fasted animals) by acting on central melanocorlating leptin and neurons that regulate feeding behavtin receptors (Tsujii and Bray, 1989; Ludwig et al., 1998). ior and body weight homeostasis. POMC neurons within the Arc contain leptin receptor mRNA (Cheung et al., 1997), and leptin regulates the levels of POMC mRNA in the Arc (Schwartz et al., 1997; Introduction Thornton et al., 1997; Mizuno et al., 1998). Recently, a novel endogenous melanocortin receptor antagonist, Leptin, produced by white adipose tissue, plays a fundaagouti-related protein (AgRP) has been identified. AgRP mental role in maintaining neuroendocrine and body is expressed in the Arc, and transgenic overexpression weight homeostasis (Zhang et al., 1994). The importance of AgRP results in obesity (Graham et al., 1997; Ollmann of leptin is illustrated by the marked abnormalities seen et al., 1997; Shutter et al., 1997). AgRP and NPY are in leptin-deficient ob/ob mice, all of which are corrected coexpressed in neurons in the medial Arc (Broberger et by leptin administration (Campfield et al., 1995; Halaas al., 1998; Hahn et al., 1998). Another recently identified et al., 1995; Pelleymounter et al., 1995). One established Arc peptide regulated by leptin levels is CART (cocainemechanism of leptin action is to decrease food intake. and amphetamine-regulated transcript) (Douglass et al., However, the neuroanatomic basis for leptin's effects 1995; Kristensen et al., 1998). CART and POMC are on food intake remains to be established. coexpressed in neurons in the lateral Arc (Elias et al., Numerous recent studies have increased the under-1998b), and like ␣-MSH, CART peptide inhibits food standing of the regulation of food intake by the hypothalintake (Lambert et al., 1997; Kristensen et al. . amus. One hypothalamic region that regulates feeding, Taken together, these findings suggest that the Arc body weight, and metabolism is the lateral hypothalis essential in the regulation of body weight and food amic area (LHA) (reviewed in Elmquist et al., 1999). The intake, and many of leptin's biological effects are likely LHA contains neurons expressing melanin-concentrating due to engaging pathways originating in the Arc. Howhormone (MCH) that innervate the entire neuraxis includever, the pathways downstream of the Arc underlying ing autonomic preganglionic neurons and the cerebral these effects are not well understood. The mechanisms by which the LHA responds to changing leptin levels are also not well understood.
PAPER Regulation of appetite: role of leptin in signalling systems for drive and satiety
BACKGROUND: The healthy regulation of appetite involves a balance between excitatory (drive) and inhibitory (satiety) processes. For many years research has concentrated on the identification of signalling systems that mediate satiety to the relative exclusion of drive-inducing biological events. However, the so-called long-term regulation of body weight has recently been given substance by the identification of a chemical signal believed to link the brain with adipose tissue stores. ANALYSIS: This signal, leptin, is in position to modulate the expression of a drive to eat. Studies on the relationship between leptin and perceived hunger, and on the eating behaviour of leptin-deficient individuals, are consistent with the intervention of leptin in a drive system. The contrast between the roles of leptin and serotonin in appetite regulation reflects the difference between drive-signalling and satiety signalling processes. CONCLUSION: It is proposed that leptin modulates the drive signals arising from the metabolic demand for energy but also shows some properties of a post-prandial satiety signal.
Leptin Regulates Energy Balance and Motivation Through Action at Distinct Neural Circuits
Biological Psychiatry, 2011
BACKGROUND-Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine.