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Cited by 342Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Leptin and the Central Nervous System Control of Glucose Metabolism

Open access
Morton, Gregory J., Schwartz, Michael W.·2011·Physiological Reviews
DOI 10.1152/physrev.00007.2010PMC PMC3379883
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Abstract

The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders.

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Written from the paper’s full text.

TL;DR

This review argues that leptin action in the central nervous system regulates glucose metabolism in addition to energy balance, with effects on hepatic insulin sensitivity and glucose production that can occur independently of food intake and body weight. It synthesizes rodent and human evidence on leptin signaling, hypothalamic and extrahypothalamic circuits, and leptin resistance in obesity.

Key findings

  • CNS leptin can correct diabetic hyperglycemia independently of insulin: i.c.v. leptin normalizes blood glucose in STZ-diabetic rats at doses ineffective peripherally, and brain leptin suppresses hepatic glucose production while increasing tissue glucose uptake despite severe insulin deficiency.
  • Leptin signaling restricted to the arcuate nucleus (ARC) is sufficient to improve peripheral insulin sensitivity without reduced food intake or body weight; this effect is PI3K-dependent, blocked by i.c.v. LY294002, and mimicked by ARC-directed constitutively active Akt/PKB.
  • ARC POMC and NPY/AgRP neurons, VMH/SF1 neurons, and hindbrain circuits including NTS/RCh and vagal pathways are implicated in leptin’s glucose effects; leptin and insulin can act on distinct POMC subpopulations, and combined deletion of insulin and leptin receptors in POMC neurons caused marked hepatic insulin resistance in female mice.
  • Diet-induced obesity is associated with leptin resistance linked to SOCS-3, PTP1B, hypothalamic inflammation, and ER stress; the review states no single mechanism is likely to predominate.

Methods

  • Narrative review synthesizing human and rodent literature on leptin signaling and CNS control of glucose metabolism; no new primary data or meta-analysis.
  • Evidence includes genetic models (ob/ob, db/db, Koletsky fak/fak, lipodystrophy, STZ/uDM), LepRb knock-in mice, Cre-loxP neuron-specific deletions/restorations, euglycemic-hyperinsulinemic clamps, i.c.v./i.v. leptin, vagotomy, and viral gene therapy.
  • Main analysis is qualitative integration of cited studies, with emphasis on mechanistic pathways (Jak-STAT, IRS-PI3K, AMPK, melanocortin, autonomic/vagal circuits).

Limitations

  • Stated: most approaches use genetic models or pharmacological leptin doses in normal animals; whether these leptin effects play a physiological role on a minute-to-minute, hour-to-hour, and day-to-day basis in genetically normal humans and animals, and whether they are neurally mediated, remain incompletely answered.
  • Stated: pancreatic clamp studies may not account for endogenous insulin secreted into the hepatic portal vein, so the liver is exposed to higher insulin levels than systemic circulation; this challenges whether neural sensing of insulin or leptin participates in control of hepatic glucose production.
  • Evident: as a review, it reports no new experimental data; several mechanisms remain unresolved, including Tyr1077/Jak2-independent LepRb signals, whether IGFBP2 is required for leptin effects, the role of SCD-1 in hepatic glucose metabolism, and whether SOCS-3 induction in leptin resistance is due to hyperleptinemia, inflammation, or both.

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Integrity signals

Registry

Crossref · 10.1152/physrev.00007.2010

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingown data

    Continuous infusion of leptin directly into the brain normalizes blood glucose levels in STZ-induced diabetic rats via a mechanism that cannot be explained by reduced food intake, increased urinary glucose losses, or recovery of pancreatic β-cells.

    “we recently found that continuous infusion of leptin directly into the brain normalizes blood glucose levels in STZ-induced diabetic rats via a mechanism that cannot be explained by reduced food intake, increased urinary glucose losses or a recovery of pancreatic β-cells.”
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  • Findingcitation

    Selective restoration of leptin receptor signaling to the ARC significantly improves peripheral insulin sensitivity via a mechanism not dependent on reduced food intake or body weight.

    “we found that selective restoration of leptin receptor signaling to the ARC significantly improved peripheral insulin sensitivity via a mechanism that was not dependent on reduced food intake or body weight (122).”
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  • Premisereasoning

    Insulin acts in the brain as an adiposity negative feedback signal.

    “Several lines of evidence support the hypothesis that in addition to leptin, the pancreatic hormone insulin also acts in the brain as an “adiposity negative feedback signal”.”
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  • Premisecitation

    Leptin and insulin circulate at levels that vary in proportion to body fat stores.

    “Both hormones circulate at levels that vary in proportion to body fat stores (4, 39)”
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    Leptin and insulin enter the CNS in proportion to their plasma levels.

    “both enter the CNS in proportion to their plasma level (160)”
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    Findingcitation

    Leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency.

    “Instead, leptin action in the brain potently suppressed hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency (67).”
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    Premisecitation

    The CNS plays an important role in the regulation of glucose metabolism, and dysfunction of this control system may contribute to metabolic consequences of obesity.

    “a parallel body of evidence suggests that the CNS plays an important role in the regulation of glucose metabolism, and that dysfunction of this control system may contribute to metabolic consequences of obesity (161).”
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    • The authors state this as an assumption: The brain continuously transduces neural, hormonal, and nutrient-related signals into responses that maintain both energy and glucose homeostasis.

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    Premisecitation

    Deficiency of leptin or insulin, or of their receptors in the CNS, results in hyperphagia, weight gain, and insulin resistance.

    “deficiency of either hormone or their respective receptors in the CNS results in hyperphagia, weight gain and insulin resistance (27, 174, 183, 212).”
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    Premisecitation

    Administration of leptin or insulin into the brain reduces food intake and body weight.

    “Administration of either peptide into the brain reduces food intake and body weight (30, 76, 200)”
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    Premisecitation

    Among leptin receptor isoforms, only LepRb appears competent for intracellular signal transduction and is critical for energy homeostasis.

    “Among the various isoforms of LepR, only the “long”, or “signaling” form, LepRb, appears to be competent for intracellular signal transduction and is critical for energy homeostasis.”
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    Premisecitation

    Phosphorylation of Tyr1138 recruits STAT3, which is phosphorylated by Jak2, dimerizes, translocates to the nucleus, and functions as a transcription factor.

    “phosphorylation of Tyr1138 recruits signal transduction and activator of transcription-3 (STAT3), which is then itself phosphorylated on tyrosine residues by Jak2 allowing it to dimerize and translocate to the nucleus where it functions as a transcription factor (6, 23, 186).”
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    Premisecitation

    Obesity is associated with insulin resistance in liver, muscle, and adipose tissue, and this insulin resistance is a cardinal feature of type 2 diabetes.

    “clear evidence, accumulated over the last forty years, that obesity is associated with insulin resistance in these tissues and that this insulin resistance is a cardinal feature of type 2 diabetes (125).”
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    Interpretationreasoning

    Energy homeostasis involves negative feedback signals that circulate in proportion to body fat and act centrally to inhibit food intake and increase energy expenditure.

    “Taken together, these data support the hypothesis that energy homeostasis involves negative feedback signals that circulate in proportion to body fat and act centrally to inhibit food intake on the one hand, and to increase energy expenditure on the other.”
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    Premisecitation

    Upon leptin binding to LepRb, Jak2 is activated and phosphorylates three tyrosine residues on LepRb (Tyr985, Tyr1077, Tyr1138), which recruit and activate downstream signaling proteins.

    “Upon leptin binding to LepRb, the tyrosine kinase Janus kinase-2 (Jak2) is activated (69), resulting in the phosphorylation of three tyrosine residues on LepRb (Tyr985, Tyr1077, Tyr1138) that in turn recruit and activate a distinct set of downstream signaling proteins.”
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    Premisecitation

    The leptin receptor contains an extracellular ligand-binding domain, a single transmembrane domain, and a cytoplasmic signaling domain, and is a member of the IL-6 receptor family of class 1 cytokine receptors.

    “The leptin receptor contains an extracellular ligand-binding domain, a single transmembrane domain and a cytoplasmic signaling domain and is member of the interleukin (IL)-6 receptor family of class 1 cytokine receptors (182).”
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    Premisecitation

    Phosphorylation of Tyr985 recruits SHP-2 to LepRb, leading to ERK pathway activation in cultured cells and recruitment of SOCS-3.

    “Phosphorylation of Tyr985 recruits SH2-domain-containing phosphatase-2 (SHP-2) to LepRb, leading to the activation of the extracellular signal regulated (ERK) signaling pathway in cultured cells, as well as the recruitment of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator of LepRb signaling (6, 21, 22).”
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    Interpretationcitation

    Tyr985 attenuates leptin action in vivo, presumably by serving as the SOCS-3 binding site.

    “These results support data from cultured cells (22) suggesting that Tyr985 attenuates leptin action in vivo, presumably by serving as the SOCS-3 binding site (24).”
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    Premisecitation

    SOCS-3 induced via the IKKβ-NFκβ pathway during cellular inflammation can contribute to leptin resistance and has been implicated in the pathogenesis of diet-induced obesity.

    “Since SOCS-3 can also be induced via the IKKβ-NFκβ pathway during cellular inflammation, this mechanism can contribute to leptin resistance in this setting (211) and has been implicated in the pathogenesis of diet-induced obesity (DIO) (87, 119, 211).”
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    Premisecitation

    Like insulin, leptin activates the IRS-PI3K pathway in the hypothalamus, and pharmacological inhibition of PI3K in the brain blocks leptin's ability to reduce food intake.

    “like insulin, leptin activates the IRS-PI3K pathway in the hypothalamus, and pharmacological inhibition of PI3K activity in the brain blocks the ability of leptin to reduce food intake (129, 130).”
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    Premisecitation

    Phosphorylation of Tyr1077 and Tyr1138 promotes recruitment, phosphorylation, and transcriptional activation of STAT5.

    “Phosphorylation of Tyr1077 and Tyr1138 promote the recruitment, phosphorylation and transcriptional activation of STAT5 (71)”
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    Premisecitation

    The SH2B1 gene locus is an obesity risk allele in human populations.

    “genome-wide scans have identified the SH2B1 gene locus as an obesity risk allele in human populations (195).”
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    Premisecitation

    Leptin has been reported to activate AMPK and mTOR signaling pathways.

    “Leptin has also been reported to activate nutrient-sensing enzymes including AMP-activated protein kinase (AMPK) (115) and mammalian target of rapamycin (mTOR) signaling pathways (41)”
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    Premisecitation

    Transplantation of body fat from wild-type animals improves insulin sensitivity in a mouse model of lipodystrophy, whereas transplantation of fat from ob/ob mice has no effect.

    “transplantation of body fat from wild-type animals improves insulin sensitivity in a mouse model of lipodystrophy, whereas transplantation of fat from ob/ob mice has no effect (38, 63).”
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    Premisecitation

    Mice with genetic leptin deficiency or leptin receptor deficiency exhibit hyperphagia, obesity, insulin resistance, and diabetes.

    “Such animals exhibit not only hyperphagia and obesity, but insulin resistance and diabetes as well (37, 57, 181, 212).”
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    Interpretationcitation

    The phenotype of s/s mice does not completely mimic that of ob/ob or db/db mice with respect to glucose metabolism, immune function, or reproduction, implying that other LepRb signals contribute to leptin action.

    “However, the phenotype of these s/s mice does not completely mimic that of either ob/ob or db/db mice with respect to glucose metabolism, immune function or reproduction (13, 14), implying that other LepRb signals must also contribute to leptin action.”
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    Premisecitation

    Mice with LepRb Tyr1138 replaced by serine (s/s) are unable to recruit STAT3 and are characterized by hyperphagia, obesity, and reduced energy expenditure.

    “Mice bearing a mutant LepRb gene in which Tyr1138 is replaced by a serine residue (s/s mice) are unable to recruit STAT3 and are characterized by hyperphagia, obesity (14) and reduced energy expenditure (12)”
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    Premisecitation

    Δ/Δ mice with truncated LepRb exhibit a phenotype resembling db/db mice in energy homeostasis, neuroendocrine, and immune function, but have delayed progression to diabetes, suggesting modest improvement in glucose homeostasis.

    “These Δ/Δ mice exhibit a phenotype that resembles db/db mice where energy homeostasis, neuroendocrine and immune function are concerned, but also are characterized by a delayed progression to diabetes, suggesting a modest improvement in glucose homeostasis (150).”
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    Premisecitation

    Mice with LepRb Tyr985 mutation (l/l) have a lean phenotype characterized by reduced food intake and adiposity and increased leptin sensitivity.

    “mutation of Tyr985 in these (l/l) mice resulted in a lean phenotype characterized by reduced food intake and adiposity, and increased leptin sensitivity (24).”
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    Premisecitation

    Leptin and insulin hyperpolarize a subset of glucose-responsive neurons in the ARC via activation of KATP channels, a mechanism blocked by a PI3K inhibitor.

    “leptin and insulin were shown to hyperpolarize a subset of “glucose-responsive” neurons in the ARC via activation of the ATP-sensitive potassium channel (KATP) (176, 177) via a mechanism that was blocked by a PI3K inhibitor (116, 177).”
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  • May combine two claims.

    Premisereasoning

    SOCS-3 is transcriptionally induced by STAT3 and causes negative feedback inhibition of leptin signaling by binding to Tyr985 of LepRb.

    “Among the genes transcriptionally induced by STAT3 is SOCS-3, which causes negative feedback inhibition of leptin signaling by binding to Tyr985 of LepRb to block its signaling (Figure 2).”
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    Premisecitation

    Uncontrolled insulin-deficient diabetes is characterized by hyperglycemia and hyperphagia, progressive loss of body fat stores, and dramatic reduction of circulating leptin and insulin.

    “uDM is characterized by both hyperglycemia and hyperphagia (102), with progressive loss of body fat stores, and with a dramatic reduction of circulating levels of leptin as well as insulin (78).”
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    Premisecitation

    In wild-type mice, intravenous leptin increases glucose turnover and glucose uptake but decreases hepatic glycogen content.

    “In wild-type mice, i.v. leptin increased glucose turnover and glucose uptake but decreased hepatic glycogen content (91).”
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    Interpretationcitation

    Intact glucagon signaling is required for diabetic hyperglycemia, and leptin-mediated decrease of plasma glucagon may mediate its effects on blood glucose.

    “glucagon receptor-null mice remain normoglycemic following treatment with alloxan to induce uDM, suggesting that intact glucagon signaling is required for diabetic hyperglycemia and hence that the leptin-mediated decrease of plasma glucagon levels may mediate its effects on blood glucose (191).”
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    Premisecitation

    Physiological leptin replacement in uDM reduces hepatic triglyceride content and gluconeogenic gene expression, restores normal insulin signal transduction in liver but not skeletal muscle or WAT, and normalizes circulating glucagon and corticosterone.

    “physiological leptin replacement in uDM reduced hepatic triglyceride content and gluconeogenic gene expression, and also restored normal insulin signal transduction in liver, but not in skeletal muscle or WAT. This intervention also normalized circulating levels of glucagon and corticosterone, both of which are elevated in uDM.”
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    Premisecitation

    Functional leptin receptors are expressed in the hippocampus, hindbrain including the NTS, pyriform cortex and other olfactory processing areas, and mesolimbic reward areas including the VTA and SN.

    “functional leptin receptors are expressed in the hippocampus, hindbrain (including the nucleus of the solitary tract (NTS)), pyriform cortex and other olfactory processing areas, and in mesolimbic areas involved in reward including the ventral tegmental area (VTA) and substantia nigra (SN) (61, 72).”
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    Interpretationown data

    This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence of a novel mechanism through which the brain normalizes diabetic hyperglycemia without the need for insulin.

    “This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver (66, 146), and offers compelling evidence of a novel mechanism through which the brain normalizes diabetic hyperglycemia without the need for insulin (67).”
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    Interpretationcitation

    At least some beneficial effects of insulin treatment in uncontrolled insulin-deficient diabetes may arise from an associated increase of leptin action because plasma leptin levels are normalized by insulin treatment in uDM rats.

    “at least some of the beneficial effects of insulin treatment may in fact arise from an associated increase of leptin action since plasma leptin levels are normalized by insulin treatment in uDM rats (78).”
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    Premisecitation

    Unilateral selective restoration of leptin signaling to the ARC in Leprneo/neo mice has only modest effects on food intake and body weight while markedly improving hyperinsulinemia and normalizing blood glucose levels.

    “unilateral, selective restoration of leptin signaling to the ARC was found to have only modest effects on food intake and body weight, while it markedly improved hyperinsulinemia and normalized blood glucose levels (40).”
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    Interpretationreasoning

    In uDM, glucose production is unrestrained and contributes importantly to diabetic hyperglycemia.

    “Consequently, in uDM, glucose production is unrestrained, and therefore contributes importantly to diabetic hyperglycemia.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In non-diabetic rats, acute intravenous leptin infusion enhances insulin's ability to suppress glucose production without affecting glucose uptake.

    “In non-diabetic rats, an acute intravenous (i.v.) leptin infusion enhanced insulin's ability to suppress glucose production without affecting glucose uptake.”
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    Premisecitation

    Koletsky fak/fak rats are characterized by obesity, hyperphagia, insulin resistance, and glucose intolerance but are not hyperglycemic.

    “These animals are characterized by obesity, hyperphagia, insulin resistance and glucose intolerance but are not hyperglycemic (57).”
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    Premisecitation

    The anti-diabetic effects of leptin in STZ-induced diabetes are accompanied by normalization of elevated glucagon levels.

    “the anti-diabetic effects of leptin in STZ-induced diabetes are accompanied by normalization of elevated glucagon levels (210).”
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    Interpretationcitation

    Physiological leptin replacement only modestly reduces blood glucose levels in uDM, demonstrating that factors beyond leptin deficiency, elevated glucagon, and elevated corticosterone are sufficient to explain hyperglycemia in this model.

    “physiological leptin replacement only modestly reduced blood glucose levels in this setting (68), demonstrating that factors beyond leptin deficiency (and elevated levels of glucagon and corticosterone) are sufficient to explain hyperglycemia in this model.”
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    Premisenone given

    In normal individuals, insulin-induced suppression of hepatic glucose production is critical for the control of blood glucose levels.

    “In normal individuals, insulin-induced suppression of HGP is critical for the control of blood glucose levels.”
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    Premisecitation

    The enhanced insulin-mediated suppression of glucose production by leptin in non-diabetic rats is due to marked suppression of hepatic glycogenolysis, whereas gluconeogenesis is paradoxically increased.

    “This enhanced insulin-mediated suppression of glucose production was due to a marked suppression of hepatic glycogenolysis, whereas gluconeogenesis was paradoxically increased (152).”
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  • May combine two claims.

    Interpretationcitation

    In STZ-induced uDM rats, hyperglycemia is only slightly improved by physiological leptin replacement despite normalized plasma glucagon levels, suggesting that glucagon normalization cannot fully explain the hypoglycemic effect of pharmacological leptin administration.

    “the observation that in rats with STZ-induced uDM, hyperglycemia is only slightly improved by physiological leptin replacement despite normalized plasma glucagon levels (68) suggests that the latter cannot fully explain the hypoglycemic effect of pharmacological leptin administration in this setting.”
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    Premisecitation

    In ob/ob mice, intravenous leptin increases glucose turnover and stimulates glucose uptake in brown adipose tissue, brain, and heart, but not in skeletal muscle or white adipose tissue.

    “In ob/ob mice, i.v. leptin also increased glucose turnover and stimulated glucose uptake in brown adipose tissue (BAT), brain and heart, but not in skeletal muscle or white adipose tissue (WAT) (29).”
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    Premisecitation

    Leptin inhibits the firing rate of NPY/AgRP neurons, depolarizes POMC neurons, and activates PI3K signaling in POMC cells.

    “leptin inhibits the firing rate of NPY/AgRP neurons (189), while simultaneously depolarizing POMC neurons (42), and also activates PI3K signaling in the latter cells (204).”
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    Interpretationcitation

    Leptin receptor-mediated STAT3 signaling is critical for energy homeostasis but not for glucose homeostasis.

    “leptin receptor-mediated STAT3 signaling appears to be critical for energy homeostasis, but not for glucose homeostasis.”
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    Interpretationreasoning

    In conditions of reduced leptin signaling, POMC neurons are inhibited while NPY/AgRP neurons are activated, promoting positive energy balance and recovery of lost weight.

    “in conditions of reduced leptin signaling (e.g. fasting or diet-induced weight loss), POMC neurons are inhibited while NPY/AgRP neurons are activated, a combination of responses that promote positive energy balance and the recovery of lost weight.”
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    Premisecitation

    Inhibition of hypothalamic AMPK lowers food intake and hepatic glucose production, while increasing hypothalamic AMPK has the opposite effect.

    “inhibition of hypothalamic AMPK (using an adenovirus expressing the dominant negative form of AMPK) lowers food intake and HGP, while increasing hypothalamic AMPK has the opposite effect (113, 209)”
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    Premisecitation

    Intrahypothalamic administration of antisense oligonucleotides to reduce insulin receptor signaling or local infusion of PI3K inhibitor LY294002 causes hepatic insulin resistance in rats.

    “either intrahypothalamic administration of antisense oligonucleotides to reduce insulin receptor signaling or local infusion of the PI3K inhibitor, LY294002, causes hepatic insulin resistance in rats (132).”
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    Premisecitation

    Blocking LCFA oxidation by increasing malonyl CoA levels in the CNS reduces food intake and hepatic glucose production.

    “pharmacological interventions designed to block LCFA oxidation by increasing malonyl CoA levels (e.g. oleic acid, fatty acid synthase (FAS) inhibitor) in the CNS reduce food intake and HGP (99, 107, 133, 147)”
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    • cites [99] source

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    • cites [133] source

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    Premisecitation

    Insulin hyperpolarizes and silences both AgRP and POMC neurons and activates PI3K signaling in both.

    “insulin hyperpolarizes and silences both AgRP and POMC neurons (96) and activates PI3K signaling in both these neuronal populations (204).”
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    • cites [96] source

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    • cites [204] source

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    Premisecitation

    Reducing hypothalamic malonyl CoA levels causes obesity and insulin resistance.

    “pharmacological interventions that reduce hypothalamic malonyl CoA levels cause obesity and insulin resistance (79).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] source

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    Premisecitation

    Effects of central insulin are blocked by PI3K inhibitor and require activation of KATP channels.

    “these effects of insulin are blocked by infusion of the PI3K inhibitor and also appear to require activation of KATP channels (135, 145).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [135] source

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    • cites [145] source

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    Premisecitation

    Selective PTEN ablation in leptin-expressing neurons is associated with increased sympathetic nerve activity to white adipose tissue and leads to remodeling of white adipose tissue toward brown adipose tissue characteristics, including increased mitochondrial content and UCP1 expression.

    “associated with increased sympathetic nerve activity to WAT and leading to a remodeling of WAT to take on characteristics of BAT, including increased mitochondrial content and UCP1 expression (144).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] source

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  • May combine two claims.

    Premisecitation

    Mice expressing a constitutively active version of STAT3 selectively in POMC neurons have a hyperphagic, obese phenotype accompanied by central insulin and leptin resistance.

    “mice expressing a constitutively-active version of STAT3 selectively in POMC neurons causes a hyperphagic, obese phenotype accompanied by central insulin and leptin resistance (58)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] source

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    Premisecitation

    i.c.v. leptin infusion reverses insulin resistance induced by short-term high-fat diet by reducing both glycogenolysis and gluconeogenesis.

    “i.c.v. leptin infusion reverses insulin resistance induced in rats by short-term exposure to a HF diet by reducing both glycogenolysis and gluconeogenesis (146)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] source

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  • May combine two claims.

    Premisecitation

    In normal rats, i.c.v. leptin administration stimulates hepatic gluconeogenesis but does not affect overall hepatic glucose production owing to a simultaneous decrease of glycogenolysis.

    “In normal rats, i.c.v. leptin administration stimulates hepatic gluconeogenesis, but fails to affect overall hepatic glucose production owing to a simultaneous decrease of glycogenolysis (106).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] source

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  • May combine two claims.

    Premisecitation

    Local administration of insulin and inhibition of fat oxidation in the arcuate nucleus increase hepatic insulin sensitivity via a mechanism requiring intact hepatic vagal innervation, and also activate hindbrain neurons within the NTS and DMX.

    “Consistent with this hypothesis, both local administration of insulin and inhibition of fat oxidation in the ARC increase hepatic insulin sensitivity via a mechanism that requires intact hepatic vagal innervation, and also activates hindbrain neurons within both the NTS and DMX (147).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] source

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  • May combine two claims.

    Premisecitation

    At pharmacological doses, central administration of leptin in normal animals increases whole body glucose turnover and glucose uptake in skeletal muscle, heart, and brown adipose tissue, but not white adipose tissue, without changes in plasma insulin or glucose levels.

    “at pharmacological doses, central administration of leptin in normal animals increases whole body glucose turnover and glucose uptake in peripheral tissues including skeletal muscle, heart and brown adipose tissue (BAT), but not white adipose tissue (WAT), without changes in plasma insulin or glucose levels (91).”
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    • cites [91] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vagal afferents play a critical role in the ability of gut-derived satiety signals such as CCK to promote the termination of a meal.

    “abundant evidence suggests that vagal afferents play a critical role in the ability of gut-derived satiety signals, such as CCK, to promote the termination of a meal”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] source

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    Premisecitation

    Heterozygous SOCS-3 deficient mice display increased leptin sensitivity and are protected against the development of obesity on a high-fat diet.

    “heterozygous SOCS-3 deficient mice display increased leptin sensitivity and are protected against the development of obesity on a HF diet (87).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] source

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    Premisecitation

    Over-expression of SOCS-3 in leptin receptor-positive neurons does not cause leptin resistance or obesity.

    “over-expression of SOCS-3 in leptin receptor-positive neurons did not (149).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] source

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    Premisecitation

    The effects of leptin on adipose tissue metabolism are STAT3-independent and appear to involve hypothalamic PI3K and sympathetic nervous system outflow.

    “these effects of leptin on adipose tissue metabolism are STAT3-independent, appearing instead to involve hypothalamic PI3K and SNS outflow (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] source

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  • May combine two claims.

    Interpretationcitation

    Leptin action in the ARC increases peripheral insulin sensitivity primarily via effects on the liver, is PI3K-dependent, and involves inhibition of hepatic gluconeogenic gene expression.

    “Thus, leptin action in the ARC increases peripheral insulin sensitivity primarily via effects on the liver, and like insulin, this effect is PI3K-dependent and involves inhibition of hepatic gluconeogenic gene expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] source

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  • May combine two claims.

    Interpretationcitation

    Leptin stimulation of gluconeogenesis involves a melanocortin-dependent pathway, while leptin inhibition of glycogenolysis occurs via a melanocortin-independent pathway.

    “pharmacological leptin stimulation of gluconeogenesis appears to involve a melanocortin-dependent pathway while leptin inhibition of glycogenolysis is proposed to occur via a melanocortin-independent pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

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  • May combine two claims.

    Premisecitation

    Restoring hypothalamic leptin signaling to Koletsky rats improves hepatic insulin sensitivity, and this effect is blocked by selective hepatic vagotomy.

    “Moreover, the beneficial effects of restoring hypothalamic leptin signaling to Koletsky rats on hepatic insulin sensitivity were blocked by selective hepatic vagotomy (66).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Reduced melanocortin signaling promotes insulin sensitivity and glucose uptake in white adipose tissue but reduces glucose utilization in brown adipose tissue and muscle, favoring increased triglyceride synthesis and storage in the body.

    “while reduced melanocortin signaling promotes insulin sensitivity and glucose uptake in WAT, it reduces glucose utilization in BAT and muscle (131), favoring increased TG synthesis and storage in the body.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] source

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  • May combine two claims.

    Premisecitation

    Obesity in humans and in rodents placed on a high-fat diet is characterized by hyperleptinemia, and the ability of leptin to suppress food intake and reduce body weight is attenuated.

    “Obesity in both humans and in rodents placed on a HF diet are characterized by hyperleptinemia, and the ability of leptin to suppress food intake and reduce body weight is attenuated (49, 81).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] source

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    • cites [81] source

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  • May combine two claims.

    Premisecitation

    Mutation of LRb Tyr985 prevents SOCS-3 action on the leptin receptor and results in mice that display increased leptin sensitivity, are lean, and are resistant to diet-induced obesity.

    “mutation of LRb Tyr985 prevents SOCS-3 action on the leptin receptor and thereby results in mice which display increased leptin sensitivity, are lean and are resistant to DIO (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

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  • May combine two claims.

    Premisecitation

    Infusion of leptin directly into the mediobasal hypothalamus during a euglycemic-hyperinsulinemic clamp suppresses expression of key de novo lipogenic enzymes in white adipose tissue and activates lipolysis and suppresses free fatty acid uptake into this tissue.

    “Infusion of leptin directly into the mediobasal hypothalamus during an euglycemic-hyperinsulinemic clamp suppressed the expression of key de novo lipogenic enzymes in WAT and also activated lipolysis and suppressed FFA uptake into this tissue (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] source

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  • May combine two claims.

    Premisecitation

    Activation of hypothalamic IKKβ/NF-κB signaling using a gene therapy approach promotes hyperphagia and weight gain and reduces leptin and insulin signaling in mice.

    “activation of hypothalamic IKKβ/NF-κB signaling using a gene therapy approach promotes hyperphagia and weight gain and reduces leptin and insulin signaling in mice (211).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [211] source

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  • May combine two claims.

    Premisecitation

    Central administration of an ER stress inhibitor suppressed hypothalamic NF-κB levels in high-fat-fed rats and lowered both food intake and body weight in diet-induced obese animals.

    “central administration of an ER stress inhibitor suppressed hypothalamic NF-κB levels in HF-fed rats and lowered both food intake and body weight in DIO animals (211).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [211] source

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    Premisecitation

    Neuronal or POMC-specific PTP1B knockout mice are protected from diet-induced obesity and exhibit increased leptin sensitivity.

    “neuronal (17) or POMC-specific (7) PTP1B knockout mice are protected from DIO and exhibit increased leptin sensitivity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims.

    Premisecitation

    Excess body adiposity is associated with activation of macrophages and associated inflammation in white adipose tissue, liver, skeletal muscle and the vasculature, and eventually with increased circulating plasma levels of pro-inflammatory cytokines.

    “Excess body adiposity has been associated with activation of macrophages and associated inflammation in a variety of peripheral tissues including WAT, liver, skeletal muscle and the vasculature and eventually is accompanied by increased circulating plasma levels of pro-inflammatory cytokines (193, 207).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • May combine two claims.

    Premisecitation

    Neuronal deletion of X-box binding protein-1 in mice increased food intake and body adiposity and is accompanied by hypothalamic leptin resistance.

    “neuronal deletion of X-box binding protein-1 (XBP-1) in mice increased food intake and body adiposity, and is accompanied by hypothalamic leptin resistance (140).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] source

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  • May combine two claims.

    Premisecitation

    Mice with cell-type specific deletion of IKKβ in AgRP neurons are protected against diet-induced obesity and exhibit reduced expression of SOCS-3 in the mediobasal hypothalamus.

    “mice with cell-type specific deletion of IKKβ in AgRP neurons, which are protected against DIO and exhibit reduced expression of SOCS-3 in the mediobasal hypothalamus (211).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [211] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ER stress and the unfolded protein response are activated in the hypothalamus of obese mice, and this effect is sufficient to inhibit leptin signaling.

    “Recent studies demonstrate that ER stress and the unfolded protein response (UPR) are activated in the hypothalamus of obese mice and that this effect is sufficient to inhibit leptin signaling (140).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] source

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  • May combine two claims.

    Premisecitation

    Interventions that reduce hypothalamic inflammation, either by reducing neuronal IKKβ signaling using gene therapy or by pharmacological administration of an IKKβ inhibitor, reduce food intake and body weight in diet-induced obese animals and maintain central leptin and insulin sensitivity.

    “interventions that reduce hypothalamic inflammation, either by reducing neuronal IKKβ signaling using a gene therapy approach (211) or by pharmacological administration of a IKKβ inhibitor, reduce food intake and body weight in DIO animals (148) and maintain central leptin and insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [211] source

      Not checked in the free run.

    • cites [148] source

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  • May combine two claims.

    Interpretationreasoning

    Hypothalamic inflammation appears to be both necessary and sufficient for high-fat-diet-induced obesity.

    “Thus, hypothalamic inflammation appears to be both necessary and sufficient for HF-induced obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Consumption of a high-fat diet induces inflammation in the hypothalamus, an effect that itself could favor weight gain by impairing the neuronal response to input from leptin and insulin.

    “Recent evidence suggests that consumption of a HFD also induces inflammation in the hypothalamus, an effect that itself could favor weight gain by impairing the neuronal response to input from leptin and insulin (184).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] source

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  • May combine two claims.

    Interpretationreasoning

    Evidence of substantial overlap in the central nervous system circuits that regulate energy balance and those that regulate glucose metabolism raises the possibility that reduced secretion, sensing, or responsiveness to afferent signals promotes both weight gain and insulin resistance.

    “Evidence of substantial overlap in the CNS circuits that regulate energy balance and those that regulate glucose metabolism raises the possibility that reduced secretion, sensing, or responsiveness to these afferent signals promotes both weight gain and insulin resistance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Whether insulin action in the brain plays a physiological role in the day-to-day regulation of glucose production by the liver or other tissues remains to be firmly established, and the same may be said about the role of leptin in glucose metabolism.

    “whether insulin action in the brain plays a physiological role in the day-to-day regulation of glucose production by the liver or other tissues remains to be firmly established, and the same may be said about the role of leptin in glucose metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Induction of ER stress in the brain of mice and rats increases food intake and body weight and blocks the anorexic effects of insulin and leptin.

    “induction of ER stress in the brain of mice and rats increases food intake and body weight and blocks the anorexic effects of insulin and leptin (140, 199).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [140] source

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    • cites [199] source

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  • May combine two claims.

    Premisecitation

    Rats fed a high-fat diet for 20 weeks exhibit both leptin resistance and hypothalamic inflammation, as measured by elevated mRNA and protein levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 resulting from activation of IKKβ and JNK-1.

    “rats fed a HFD for 20-weeks exhibit both leptin resistance and hypothalamic inflammation, as measured by elevated mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) resulting from activation of IKKβ and JNK-1 (45, 148, 211).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [45] source

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    • cites [148] source

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    • cites [211] source

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  • May combine two claims.

    Interpretationnone given

    Leptin plays an important role in the control not only of energy homeostasis but also of glucose homeostasis, and the central nervous system is implicated in both leptin effects.

    “we have highlighted evidence that the adiposity signal leptin plays an important role in the control not only of energy homeostasis, but of glucose homeostasis as well, and that the CNS is implicated in both leptin effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    No single mechanism is likely to predominate in the pathogenesis of obesity-associated leptin resistance, and numerous mechanisms probably contribute in ways that are challenging to disarticulate.

    “no single mechanism is likely predominate in the pathogenesis of obesity-associated leptin resistance and, like insulin resistance in peripheral tissues, it seems probable that numerous mechanisms contribute in ways that are challenging to disarticulate.”
    Quote in the paperNot a substantial claim
84 of 84

  • The authors state this as an assumption.

    The brain continuously transduces neural, hormonal, and nutrient-related signals into responses that maintain both energy and glucose homeostasis.

    “The brain continuously transduces input from neural, hormonal and nutrient-related signals into responses that maintain both energy- and glucose-homeostasis.”

  • The authors state this as an assumption.

    Afferent signals such as insulin and leptin convey information to the brain regarding long-term energy stores, while glucose and free fatty acids convey short-term energy availability.

    “Afferent signals such as the hormones insulin and leptin convey information to the brain regarding long-term energy stores, while information regarding short-term energy availability is conveyed by nutrient-related signals such as glucose and free-fatty acids (FFA).”

  • The authors state this as an assumption.

    In response to neural, hormonal, and nutrient-related input, the brain adjusts output systems that control food intake, energy expenditure, hepatic insulin sensitivity, and glucose uptake.

    “In response to this input, the brain makes adjustments to output systems that control food intake, energy expenditure, hepatic insulin sensitivity and glucose uptake (Figure 1).”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Insulin, while peripherally lowering blood glucose and stimulating appetite, inhibits appetite centrally in a leptin-like manner.

    “Insulin, while peripherally lowering blood glucose and stimulating appetite, inhibits appetite centrally in a leptin-like manner.78”

    From Interacting epidemics? Sleep curtailment, insulin resistance, and obesity (2012) · cites this paper as [78]

  • Leptin activates POMC/CART neurons, which induces hunger and inhibits NPY/AgRP neurons, which induces satiety.

    “Leptin activates POMC/CART neurons, which induces hunger and inhibits NPY/AgRP neurons,77,78 which induces satiety.”

    From Interacting epidemics? Sleep curtailment, insulin resistance, and obesity (2012) · cites this paper as [78]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting descriptions of the neurons targeted by PTEN deletion

    Minor

    Adjacent sentences describe the same PTEN-deletion phenotype as arising from deletion in leptin-receptor-expressing neurons and in leptin-expressing neurons. These name different target populations.

  • Conflicting claims about whether STAT3 is required for leptin's glucose effects

    Minor

    One section says leptin receptor-mediated STAT3 signaling is not critical for glucose homeostasis, while another says intact STAT3 signaling is required for hypothalamic leptin to regulate glucose metabolism. The latter claim is not qualified as referring to a narrower effect.

2 of 2

Cites

Flagged first, then by citations

6 of the 223 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

  1. Banting FG, 1990, J Lab Clin Med, 115, 254
  2. Bernard C, 1854, Lecons de physiologie experimentale appliqués à là medecine
  3. Koch L, 2008, J Clin Invest, 118, 2132
  4. Maghnie M, 2003, Horm Res, 59, 42
  5. Myers MG, Trends Endocrinol Metab

Cited by

Sorted by citations

Related

Authors
Morton, G. J., & Schwartz, M. W.
Affiliations
University of Washington (US)
Corresponding author
Morton, Gregory J.
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2011-04
Volume
91
Issue
2
Pages
389-411
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
DOI
10.1152/physrev.00007.2010
PMC
PMC3379883
OpenAlex
W1964489271
Semantic Scholar
62ddf5107910cc11bee87a4c5903a9eecc02a748
Cited by
338
References
223
Citations by year
2026: 8 · 2025: 8 · 2024: 8 · 2023: 9 · 2022: 15 · 2021: 24 · 2020: 22 · 2019: 18 · 2018: 27 · 2017: 32 · 2016: 29 · 2015: 28 · 2014: 36 · 2013: 32 · 2012: 33
FWCI
3.73
Type
journal article
Language
en
Open access
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1u24dk076126-01)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-083042, U24-DK076126, P30-DK 17047, DK068384, DK 035816, DK052989, R01DK052989, P01DK068384, R01DK090320, P30DK035816, P30DK017047, R01DK083042)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
leptin, central nervous system, glucose metabolism, blood glucose regulation, body fat regulation, diabetes treatment, hypothalamic regulation
MeSH terms
Adipose Tissue, Animals, Central Nervous System, Diabetes Mellitus, Glucose, Homeostasis, Humans, Insulin, Nerve Net, Nutritional Physiological Phenomena, Obesity, Signal Transduction, Phosphatidylinositol 3-Kinases, Leptin, Adiposity, Janus Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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