Leptin targets in the mouse brain

Scott, Michael M.; Lachey, Jennifer; Sternson, Scott M.; Lee, Charlotte E.; Elias, Carol F.; Friedman, Jeffrey M.; Elmquist, Joel K.

doi:10.1002/cne.22025

Cited by 415 publications

(404 citation statements)

References 56 publications

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“…However, given that the excessive food intake that contributes to human obesity is generally not driven by metabolic need, it is critical to examine and better define the neural basis of nonhomeostatic controls on food intake. As leptin receptors (LepRb) are also expressed in brain regions associated with reward and cognitive processes (eg Scott et al, 2009), determining the extent to which leptin signaling in these extra-hypothalamic and extra-hindbrain regions contributes to the non-homeostatic control of feeding is a priority and the subject of this paper.…”

Section: Introductionmentioning

confidence: 99%

“…LepRb are expressed in the hippocampus (Huang et al, 1996;Scott et al, 2009), a brain structure involved with learning and memory function that has more recently been linked with food intake control (see references Davidson et al (2005) (2007) and Kanoski and Davidson (2011) for reviews). Previous research establishes a role for hippocampal LepRb signaling in learning and memory function.…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Kanoski

Hayes

Greenwald

et al. 2011

Neuropsychopharmacol

132

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The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 mg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 mg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Kanoski

Hayes

Greenwald

et al. 2011

Neuropsychopharmacol

132

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“…A number of hypothalamic neurons and extrahypothalamic neurons express functional leptin receptor (10,11). Among these neurons, POMC and agouti-related protein (AgRP) neurons are two key arcuate neuronal subtypes.…”

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confidence: 99%

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Olofsson

Unger

Cheung

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

111

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Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agouti-related protein (AgRP)-expressing neurons precede proopiomelanocortin neurons in developing diet-induced cellular leptin resistance. High-fat diet-induced up-regulation of suppressor of cytokine signaling-3 (SOCS3) occurs in AgRP neurons before proopiomelanocortin and other hypothalamic neurons. SOCS3 expression in AgRP neurons increases after 2 d of high-fat feeding, but reduces after switching to a low-fat diet for 1 d. Consistently, transgenic overexpression of SOCS3 in AgRP neurons produces metabolic phenotypes resembling those observed after short-term high-fat feeding. We further show that AgRP neurons are the predominant cell type situated outside the blood-brain barrier in the mediobasal hypothalamus. AgRP neurons are more responsive to low levels of circulating leptin, but they are also more prone to development of leptin resistance in response to a small increase in blood leptin concentrations. Collectively, these results suggest that AgRP neurons are able to sense slight changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Furthermore, modulation of SOCS3 expression in AgRP neurons may play a dynamic and physiological role in metabolic fine tuning in response to short-term changes of nutritional status.M ost common forms of obesity, including diet-induced obesity, are associated with hyperleptinemia and impairment of leptin signaling in hypothalamic neurons, the hallmark feature of cellular leptin resistance. Suppressor of cytokine signaling-3 (SOCS3), a direct transcriptional product of STAT3, is up-regulated in the hypothalamus of diet-induced obese animals (1, 2). Mice with heterozygous mutation of the Socs3 gene, neuronal, or proopiomelanocortin (POMC)-specific deletion of the Socs3 gene are hypersensitive to leptin and resistant to diet-induced obesity (3-5). Conversely, up-regulation of SOCS3 in POMC neurons of chow-fed mice leads to increased body adiposity (6). In addition, wide-spread up-regulation of SOCS3 has been shown to be associated with neuronal inflammation in diet-induced obese animals (7). Thus SOCS3, which is up-regulated in chronic obesity, is commonly thought to play a pathophysiological role in obesity-associated leptin resistance.Multiple neuronal subtypes in several regions of the hypothalamus, including the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamic area, have been implicated in the regulation of energy balance and leptin action (8,9). A number of hypothalamic neurons and extrahypothalamic neurons express functional leptin receptor (10, 11). Among these neurons, POMC and agouti-related protein (AgRP) neurons are two key arcuate neuronal subtypes. POMC and AgRP neu...

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“…10,16,23,33,34 Leptin, a 16 kD hormone, is transported across the blood brain barrier (BBB) by an active receptor-mediated process to diverse subpopulations of leptin receptor-expressing neurons in the hypothalamic nuclei ( Figure 1). 10,33,41,[43][44][45] These neuronal subpopulations coexpress neuropeptides and amino-acid neurotransmitters that together constitute an appetite regulating network (ARN) and energy regulating network (EEN) in the basal hypothalamus. 10,33,34 These interconnected circuitries are normally engaged to regulate appetite and energy expenditure.…”

Section: Introductionmentioning

confidence: 99%

“…10,33 How these two circuitries relay appropriate signals under the direction of circulating leptin for weight homeostasis has been reviewed extensively. 10,16,23,33,35,42,45,46 More recently, a third leptin-responsive circuit in the hypothalamus, the fat accrual network (FAN) that operates independent of appetite regulating network and EEN to augment glucose metabolism and disposal in the periphery on the one hand, and restrain pancreatic insulin secretion, on the other hand, has been identified ( Figure 1). 10 Whether this hypothalamic circuit may have a significant role in the pathogenesis of diabetes is reinforced by the following evidence:…”

Section: Introductionmentioning

confidence: 99%

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

Kalra

2011

Gene Ther

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The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

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Leptin targets in the mouse brain

Cited by 415 publications

References 56 publications

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

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