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Cited by 228Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons

Open access
Huo, Lihong, Gamber, Kevin, Greeley, Sarah, Silva, Jose, Huntoon, Nicholas, Leng, Xing-Hong, Bjørbæk, Christian·2009·Cell Metabolism
DOI 10.1016/j.cmet.2009.05.003PMC PMC2730605
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Abstract

Summary Leptin plays a pivotal role in regulation of energy balance. Via unknown central pathways leptin also affects peripheral glucose homeostasis and locomotor activity. We hypothesized that specifically Pro-opiomelanocortin (POMC) neurons mediate those actions. To examine this possibility we applied Cre-Lox technology to express leptin receptors (ObRb) exclusively in POMC neurons of the morbidly obese, profoundly diabetic, and severely hypoactive leptin receptor deficient Leprdb/db mice. We here show that expression of ObRb only in POMC neurons leads to a marked decrease in energy intake and a modest reduction in body weight in Leprdb/db mice. Remarkably, blood glucose levels are entirely normalized. This normalization occurs independently of changes in food intake and body weight. In addition, physical activity is greatly increased despite profound obesity. Our results suggest that leptin signaling exclusively in POMC neurons is sufficient to stimulate locomotion and prevent diabetes in the severely hypoactive and hyperglycemic obese Leprdb/db mice.

AI snapshot

Written from the paper’s full text.

TL;DR

Expressing leptin receptors (HA-ObRb) exclusively in POMC neurons of leptin-receptor-deficient Leprdb/db mice normalized blood glucose and roughly doubled locomotor activity, despite persistent severe obesity. These effects occurred largely independently of reduced food intake and body weight.

Key findings

  • Blood glucose was fully normalized in 5-week-old HA-ObRb/Pomc-Cre/Leprdb/db mice; pair-feeding Leprdb/db mice a ~30% reduced intake for 3 weeks did not reduce hyperglycemia, indicating glucose correction was independent of energy intake and body weight.
  • Food intake fell 30–40% and body weight decreased 10–15% versus Leprdb/db mice, but body weight remained 65–90% above wild-type mice; whole-body energy expenditure did not differ.
  • Locomotor activity increased ~100% versus Leprdb/db mice and was not statistically different from lean wild-type mice.
  • Serum insulin was reduced by 60%, insulin tolerance improved (p=0.021 vs Leprdb/db), total endocrine islet mass increased 2.5-fold, and hypothalamic α-MSH peptide levels increased 3.5-fold versus Leprdb/db mice.

Methods

  • Cre-Lox transgenic strategy: HA-tagged ObRb was expressed in POMC neurons by mating HA-ObRb transgenic mice with Pomc-Cre mice, then crossed onto Leprdb/db background to generate HA-ObRb/Pomc-Cre/Leprdb/db mice.
  • Phenotyping included immunohistochemistry for HA, β-endorphin, P-STAT3, and α-MSH; leptin-induced STAT3 phosphorylation counts; blood glucose, insulin, leptin, triglycerides; insulin and glucose tolerance tests; pancreas histology; CLAMS indirect calorimetry and locomotor activity; hypothalamic neuropeptide mRNA by real-time PCR and peptide enzyme immunoassays.
  • Data are means ± SEM; significance set at p ≤ 0.05; Student’s t-tests, and for insulin tolerance tests general linear models with one-way ANOVA and protected least significant-differences.

Limitations

  • The paper states the specific mechanism by which POMC leptin signaling normalizes blood glucose is unknown and likely involves neuroendocrine and/or autonomic actions; the relative contributions of the melanocortin system, pancreas, muscle, and liver remain to be determined.
  • The paper states that a possible role of NTS POMC neurons cannot be excluded, although the authors conclude arcuate POMC neurons are responsible; it also notes only ~50% of hypothalamic POMC neurons expressed functional HA-leptin receptors, with the reason unclear.
  • The paper states that whether increased islet mass is a direct result of leptin action via POMC neurons or an indirect consequence of altered metabolic state/incretin action remains to be elucidated, and the extent to which increased locomotion contributes to lowered glucose remains to be determined.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2009.05.003

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 58 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Expression of ObRb only in POMC neurons leads to a marked decrease in energy intake in Leprdb/db mice.

    “We here show that expression of ObRb only in POMC neurons leads to a marked decrease in energy intake and a modest reduction in body weight in Leprdb/db mice.”
    • Also stated in: § Leptin signaling in POMC neurons of Leprdb/db mice reduces body weight and food intake · plain
      “Food intake was markedly reduced (30–40%) in HA-ObRb/Pomc-Cre/Leprdb/db mice compared to Leprdb/db control mice, but remained significantly higher than wild type mice (Figure 3C and 3D).”
    Quote in the paperSubstantial claim
  • Findingown data

    HA-ObRb/Pomc-Cre/Leprdb/db mice had modestly increased hypothalamic POMC mRNA.

    “HA-ObRb/Pomc-Cre/Leprdb/db mice had modestly increased hypothalamic POMC mRNA (Figure 6A) consistent with a role of leptin signaling to stimulate Pomc gene expression (Munzberg et al., 2003; Thornton et al., 1997).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Munzberg et al., 2003 source

      Not checked in the free run.

    • cites Thornton et al., 1997 source

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  • Findingown data

    P-STAT3 was not detected in the VMH, DMH, and PMV nuclei of HA-ObRb/Pomc-Cre/Leprdb/db mice.

    “Importantly, P-STAT3 was not detected in the ventromedial (VMH), the dorsomedial (DMH), and the premammillary (PMV) nuclei of HA-ObRb/Pomc-Cre/Leprdb/db mice, regions known to express P-STAT3 in leptin-treated wild type mice (Figure 2C)(Munzberg et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Munzberg et al., 2004 source

      Not checked in the free run.

  • Findingown data

    HA-ObRb/Pomc-Cre mice on a pure FVB background were indistinguishable from wild type littermates with regard to body weight, food intake, circulating glucose and insulin, and glucose- and insulin-tolerance.

    “Similarly, HA-ObRb/Pomc-Cre mice on a pure FVB background were indistinguishable from wild type littermates with regard to body weight, food intake, circulating glucose and insulin, and glucose- and insulin-tolerance (Supplemental Figures 4 and 5).”
    Quote in the paperSubstantial claim
  • Findingown data

    Pair-feeding (~30% intake reduction) of eight weeks old female Leprdb/db mice to ad libitum fed HA-ObRb/Pomc-Cre/Leprdb/db littermates for three weeks did not reduce hyperglycemia in Leprdb/db mice.

    “As shown in Figure 4E, this food restriction did not reduce hyperglycemia in Leprdb/db mice.”
    Quote in the paperSubstantial claim
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    Total hypothalamic α-MSH peptide levels were 3.5 fold increased in HA-ObRb/Pomc-Cre/Leprdb/db mice relative to Leprdb/db mice, and were similar to wild type levels.

    “Moreover, total hypothalamic α-MSH peptide levels were 3.5 fold increased in HA-ObRb/Pomc-Cre/Leprdb/db mice relative to Leprdb/db mice, and were similar to wild type levels (Figure 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Leptin did not induce P-STAT3 in the hypothalamus of HA-ObRb/Leprdb/db control mice or Pomc-Cre/Leprdb/db control mice.

    “As predicted, leptin did not induce P-STAT3 in the hypothalamus of HA-ObRb/Leprdb/db control mice (Figure 2A) or Pomc-Cre/Leprdb/db control mice (not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Body weights of HA-ObRb/Pomc-Cre/Leprdb/db mice were slightly decreased (10-15%) as compared to Leprdb/db mice, but remained greatly increased (65-90%) relative to wild type mice.

    “Body weights of HA-ObRb/Pomc-Cre/Leprdb/db mice were slightly decreased (10–15%) as compared to Leprdb/db mice, but remained greatly increased (65–90%) relative to wild type mice (Figure 3A and 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Insulin tolerance was significantly improved in HA-ObRb/pomc-Cre/Leprdb/db mice relative to Leprdb/db mice over time (p=0.021), and trended towards a decrease (0-30 min) compared to wild type mice (p=0.097).

    “Insulin tolerance was significantly improved in HA-ObRb/pomc-Cre/Leprdb/db mice relative to Leprdb/db mice over time (p=0.021), and trended towards a decrease (0–30 min) compared to wild type mice (p=0.097)(Figure 4H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The activity of HA-ObRb/Pomc-Cre/Leprdb/db mice was not statistically different from lean wild type mice, although there was a trend towards a reduction.

    “The activity of HA-ObRb/Pomc-Cre/Leprdb/db mice was not statistically different from lean wild type mice, although there was a trend towards a reduction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HA immunoreactive cells were found in the ARC of HA-ObRb/Pomc-Cre mice, but not in brains from HA-ObRb control mice.

    “As expected, HA immunoreactive (IR) cells were found in the ARC of HA-ObRb/Pomc-Cre mice (Figure 1B), but not in brains from HA-ObRb control mice (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Body length and lean mass were not different among HA-ObRb/Pomc-Cre/Leprdb/db, Leprdb/db, and wild type groups.

    “Body length (Table 1) and lean mass was not different among these groups (not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Food intake was markedly reduced (30-40%) in HA-ObRb/Pomc-Cre/Leprdb/db mice compared to Leprdb/db control mice, but remained significantly higher than wild type mice.

    “Food intake was markedly reduced (30–40%) in HA-ObRb/Pomc-Cre/Leprdb/db mice compared to Leprdb/db control mice, but remained significantly higher than wild type mice (Figure 3C and 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Serum insulin levels were reduced by 60% in HA-ObRb/Pomc-Cre/Leprdb/db mice compared to Leprdb/db control mice, but elevated relative to control animals.

    “Serum insulin levels were reduced by 60% in HA-ObRb/Pomc-Cre/Leprdb/db mice compared to Leprdb/db control mice, but elevated relative to control animals (Figure 4G).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    The HA-tag did not interfere with STAT3 activation by ObRb in transfected cells.

    “The HA-tag did not interfere with STAT3 activation by ObRb in transfected cells (not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Total endocrine mass was increased by 2.5 fold in HA-ObRb/Pomc-Cre/Leprdb/db mice as compared to both Leprdb/db and wild type mice, and was caused by increased islet size.

    “Total endocrine mass was increased by 2.5 fold in HA-ObRb/Pomc-Cre/Leprdb/db mice as compared to both Leprdb/db and wild type mice, and was caused by increased islet size.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    60% (+/−5%) of POMC neurons in leptin-treated wild type mice and less than 2% of POMC neurons in Leprdb/db mice expressed P-STAT3.

    “Further, 60% (+/−5%) of POMC neurons in leptin-treated wild type mice and less than 2% of POMC neurons in Leprdb/db mice expressed P-STAT3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    56% (+/−24%) of POMC neurons expressed P-STAT3, and 88% (+/−8%) of the P-STAT3 IR cells were POMC neurons in leptin-treated HA-ObRb/Pomc-Cre/Leprdb/db mice.

    “Counts of β-Endorphin and P-STAT3 positive neurons (Figure 2D) in leptin-treated HA- ObRb/Pomc-Cre/Leprdb/db mice showed that 56% (+/−24%) of POMC neurons expressed P-STAT3, and that 88% (+/−8%) of the P-STAT3 IR cells were POMC neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    P-STAT3 IR cells were detected in the NTS of HA-ObRb/Pomc-Cre/Leprdb/db mice despite lack of detectable HA positive neurons in this region.

    “Despite lack of detectable HA positive neurons in this region (not shown), P-STAT3 IR cells were detected in the NTS of HA-ObRb/Pomc-Cre/Leprdb/db mice (not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was a marked 30-40% reduction in energy intake in mice expressing leptin receptors solely in POMC neurons relative to Leprdb/db mice, but no detected changes in whole body O2 consumption.

    “We found a marked 30–40% reduction in energy intake in mice expressing leptin receptors solely in POMC neurons relative to Leprdb/db mice, but did not detect changes in whole body O2 consumption.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Ventricular infusion of α-MSH into rats enhances acute insulin-stimulated peripheral glucose uptake and reduces hepatic glucose production, while a melanocortin receptor antagonist exerts opposite effects.

    “In addition, ventricular infusion of α-MSH into rats enhances acute insulin-stimulated peripheral glucose uptake and reduces hepatic glucose production, while a melanocortin receptor antagonist exerts opposite effects (Obici et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Obici et al., 2001 source

      Not checked in the free run.

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    Premisecitation

    Mice lacking leptin receptors only in POMC or AgRP neurons are mildly obese, demonstrating that both groups of cells are partly required for maintenance of body weight homeostasis by leptin.

    “Mice lacking leptin receptors only in POMC or AgRP neurons are mildly obese, demonstrating that both groups of cells are partly required for maintenance of body weight homeostasis by leptin (Balthasar et al., 2004; van de Wall et al., 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Balthasar et al., 2004 source

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    • cites van de Wall et al., 2007 source

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    Premisecitation

    Absence of leptin or leptin receptors in Lepob/ob or Leprdb/db mice results in morbid obesity, hyperphagia, severe hyperglycemia and insulin resistance, and marked hypoactivity.

    “The absence of leptin or leptin receptors in Lepob/ob mice or Leprdb/db mice respectively, results in morbid obesity, hyperphagia, severe hyperglycemia and insulin resistance, and marked hypoactivity (Chen et al., 1996; Coleman, 1978; Lee et al., 1996; Pelleymounter et al., 1995; Tartaglia et al., 1995; Zhang et al., 1994).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chen et al., 1996 source

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    • cites Coleman, 1978 source

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

    Premisecitation

    Insulin resistance is present before the onset of obesity in melanocortin-4-receptor deficient mice.

    “Insulin resistance is present before the onset of obesity in melanocortin-4-receptor deficient mice (Fan et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fan et al., 2000 source

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

    Premisecitation

    Leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models characterized by low serum leptin levels and severe insulin resistance.

    “Moreover, leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models which are characterized by low serum leptin levels and by severe insulin resistance (Oral et al., 2002; Petersen et al., 2002; Shimomura et al., 1999).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Oral et al., 2002 source

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    • cites Petersen et al., 2002 source

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    • cites Shimomura et al., 1999 source

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  • May combine two claims.

    Premisecitation

    POMC neurons are depolarized by leptin, leading to release of α-MSH, which mediates anorexigenic effects through activation of melanocortin receptors.

    “POMC neurons are depolarized by leptin, leading to release of α-melanocyte stimulating hormone (α-MSH), a POMC-derived neuropeptide that mediates its anorexigenic effects through activation of melanocortin receptors (Cone, 2005; Cowley et al., 2001; Schwartz et al., 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cone, 2005 source

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    • cites Cowley et al., 2001 source

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    • cites Schwartz et al., 2000 source

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

    Premisecitation

    Intracerebroventricular leptin can acutely stimulate glucose uptake in skeletal muscle.

    “In addition, intracerebroventricular leptin can acutely stimulate glucose uptake in skeletal muscle (Cusin et al., 1998; Haque et al., 1999; Kamohara et al., 1997; Minokoshi et al., 1999)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cusin et al., 1998 source

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    • cites Haque et al., 1999 source

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    • cites Kamohara et al., 1997 source

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    Premisecitation

    Intracerebroventricular leptin can inhibit hepatic glucose production.

    “and inhibit hepatic glucose production (Pocai et al., 2005; van den Hoek et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pocai et al., 2005 source

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    • cites van den Hoek et al., 2008 source

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    Premisecitation

    AgRP is an endogenous melanocortin receptor antagonist that potently stimulates feeding.

    “AgRP is an endogenous melanocortin receptor antagonist that potently stimulates feeding (Ollmann et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ollmann et al., 1997 source

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    Premisecitation

    Long-term impairment of central melanocortin receptor action in mice results in marked obesity, hyperinsulinemia, and late-onset hyperglycemia.

    “Long-term impairment of central melanocortin receptor action in mice results in marked obesity, hyperinsulinemia, and late-onset hyperglycemia (Huszar et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huszar et al., 1997 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Restoration of leptin-receptors in arcuate neurons greatly increases voluntary locomotor activity in Leprdb/db mice.

    “Restoration of leptin-receptors in arcuate neurons greatly increases voluntary locomotor activity in Leprdb/db mice (Coppari et al., 2005), but the specific neurons mediating this action remain unknown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Coppari et al., 2005 source

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  • May combine two claims.

    Interpretationown data

    Leptin receptor signaling in POMC neurons is sufficient to exert remarkable control of serum glucose concentrations and locomotion.

    “In contrast, our studies demonstrate that leptin receptor signaling in POMC neurons is sufficient to exert remarkable control of serum glucose concentrations and locomotion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The total islet mass did not correlate with circulating insulin levels between Leprdb/db and HA-ObRb/Pomc-Cre/Leprdb/db groups, indicating differential β-cell regulation and/or functionality.

    “The total islet mass did not correlate with circulating insulin levels between Leprdb/db and HA-ObRb/Pomc-Cre/Leprdb/db groups, indicating differential β-cell regulation and/or functionality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Central leptin administration can acutely increase muscle glucose uptake and decrease hepatic glucose production through altered autonomic output.

    “Consistent with this, central leptin administration can acutely increase muscle glucose uptake (Kamohara et al., 1997) and decrease hepatic glucose production (van den Hoek et al., 2008) through altered autonomic output (Haque et al., 1999).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kamohara et al., 1997 source

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    • cites van den Hoek et al., 2008 source

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    • cites Haque et al., 1999 source

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  • May combine two claims.

    Premisecitation

    Deletion of ObRb from only POMC neurons of lean mice does not lead to hyperglycemia or hypoactivity, suggesting that leptin receptors in POMC neurons are not required for normal regulation of glucose balance and locomotion.

    “Interestingly, deletion of ObRb from only POMC neurons of lean mice does not lead to hyperglycemia (Balthasar et al., 2004) or hypoactivity (Shi et al., 2008), suggesting that leptin receptors in POMC neurons are not required for normal regulation of glucose balance and locomotion.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Balthasar et al., 2004 source

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    • cites Shi et al., 2008 source

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  • May combine two claims.

    Interpretationown data

    The normalization of blood glucose is a direct consequence of leptin action in POMC neurons and is not secondary to differences in energy consumption or body weight.

    “Our data suggest that the normalization is a direct consequence of leptin action in POMC neurons and is not secondary to differences in energy consumption or body weight.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The pair-feeding paradigm greatly impacted the metabolic status of Leprdb/db mice and this alone was insufficient to attenuate hyperglycemia.

    “altogether demonstrating that the pair-feeding paradigm greatly impacted the metabolic status of Leprdb/db mice and that this alone was insufficient to attenuate hyperglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The central melanocortin pathway can increase sympathetic drive to peripheral tissues and enhance insulin-dependent glucose disposal.

    “Furthermore, the central melanocortin pathway can increase sympathetic drive to peripheral tissues and enhance insulin-dependent glucose disposal (Brito et al., 2007; Heijboer et al., 2005; Rahmouni et al., 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brito et al., 2007 source

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    • cites Heijboer et al., 2005 source

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    • cites Rahmouni et al., 2003 source

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  • May combine two claims.

    Interpretationown data

    Leptin signaling exclusively in POMC neurons is sufficient to stimulate locomotion and prevent diabetes in the severely hypoactive and hyperglycemic obese Leprdb/db mice.

    “Our results suggest that leptin signaling exclusively in POMC neurons is sufficient to stimulate locomotion and prevent diabetes in the severely hypoactive and hyperglycemic obese Leprdb/db mice.”
    • Also stated in: § Discussion · plain
      “We show here that expression of ObRb only in POMC neurons is sufficient to correct diabetes and drastically stimulate locomotor activity of the leptin receptor-deficient Leprdb/db mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    POMC neurons play a partial role in attenuating food intake by leptin, but have little if any role in leptin's action to increase energy expenditure.

    “This suggests that POMC neurons play a partial role in attenuating food intake by leptin, but have little if any role in leptin’s action to increase energy expenditure (Hwa et al., 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hwa et al., 1997

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  • May combine two claims.

    Interpretationreasoning

    Arcuate POMC neurons, but not NTS POMC neurons, are responsible for mediating the effects of leptin on body weight, food intake, serum glucose, and locomotor activity in HA-ObRb/Pomc-Cre/Leprdb/db mice.

    “we conclude that arcuate POMC neurons, but not NTS POMC neurons, are responsible for mediating those effects of leptin.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The phenotype of HA-ObRb/Pomc-Cre/Leprdb/db mice is directly comparable to the phenotype resulting from arcuate-specific restoration of leptin receptors in Coppari et al. (2005).

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

    Study design and conductnone given

    The housekeeping gene cyclophilin was used for normalization in real-time PCR.

    “The housekeeping gene cyclophilin was used for normalization.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A role of skeletal muscle AMP-activated protein kinase (AMPK) in mediating exercise-dependent stimulation of insulin sensitivity and glucose uptake has been reported.

    “A role of skeletal muscle AMP-activated protein kinase (AMPK) in mediating exercise-dependent stimulation of insulin sensitivity and glucose uptake has been reported (Musi and Goodyear, 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Musi and Goodyear, 2003

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  • May combine two claims.

    Interpretationown data

    Leptin signaling specifically in hypothalamic POMC neurons is sufficient to correct diabetes and greatly increase locomotion in Leprdb/db mice.

    “our data show that leptin signaling specifically in hypothalamic POMC neurons is sufficient to correct diabetes and greatly increase locomotion in Leprdb/db mice”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Exercise training increases insulin-sensitivity and improves glucose homeostasis.

    “Exercise training increases insulin-sensitivity and improves glucose homeostasis (Hespel et al., 1996; Ryder et al., 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hespel et al., 1996 source

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    • cites Ryder et al., 2001 source

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

    Study design and conductnone given

    Animal care and procedures were approved by the Institutional Animal Care and Use Committee at Beth Israel Deaconess Medical Center.

    “Animal care and procedures were approved by the Institutional Animal Care and Use Committee at Beth Israel Deaconess Medical Center.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Leptin signaling in approximately 50% of hypothalamic POMC neurons is sufficient to normalize blood glucose levels and stimulate physical activity.

    “These data combined therefore suggest that leptin signaling in ~50% of hypothalamic POMC neurons are sufficient to normalize blood glucose levels and stimulate physical activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The phenotype resulting from unilateral restoration of endogenous leptin receptors in arcuate neurons is strikingly similar to that of HA-ObRb/Pomc-Cre/Leprdb/db mice.

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

    Interpretationreasoning

    A possible role of NTS POMC neurons in mediating some phenotypic changes in HA-ObRb/Pomc-Cre/Leprdb/db animals cannot be excluded.

    “a possible role of these cells in mediating some of the phenotypic changes in HA-ObRb/Pomc-Cre/Leprdb/db animals cannot be excluded.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deletion of ObRb in the ventromedial hypothalamus (VMH) in 12 wks old mice increases body weight by ~10% and a combined loss in POMC and VMH neurons increases weight by 25%, suggesting additive effects.

    “In further support of this, deletion of ObRb in the ventromedial hypothalamus (VMH) in 12 wks old mice increases body weight by ~10% and a combined loss in POMC and VMH neurons increases weight by 25%, suggesting additive effects (Dhillon et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dhillon et al., 2006 source

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

    Premisecitation

    Central administration of melanocortin receptor agonists is sufficient to activate muscle AMPK phosphorylation in mice.

    “In addition, central administration of melanocortin receptor agonists is sufficient to activate muscle AMPK phosphorylation in mice (Tanaka et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tanaka et al., 2007 source

      Not checked in the free run.

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

    Study design and conductnone given

    Only littermates with the same mixed genetic background (FVB/C57BLKSJ) were compared, except for Supplemental Figures 4 and 5 where pure FVB non-Leprdb/db mice were studied.

    “Only littermates with the same mixed genetic background (FVB/C57BLKSJ) were compared, except for Supplemental Figures 4 and 5 where pure FVB non-Leprdb/db mice were studied.”
    Quote in the paperNot a substantial claim
46 of 46

  • The paper relies on this without support.

    The specific arcuate neurons responsible for mediating leptin's effects on glucose balance and voluntary locomotor activity are unspecified.

    “Genetic studies in mice suggest that the arcuate hypothalamic nucleus plays a major role in mediating effects of leptin on glucose balance and on voluntary locomotor activity (Coppari et al., 2005), however the specific arcuate neurons responsible remain unspecified.”

  • The paper relies on this without support.

    The extent to which POMC neuronal action can prevent severe hyperglycemia is unknown.

    “However the extent to which POMC neuronal action can prevent severe hyperglycemia is unknown.”

  • The paper relies on this without support.

    The pair-feeding paradigm and weight-matching adequately isolate the effects of leptin signaling in POMC neurons from changes in energy intake and body weight.

    “To examine whether this reduction in circulating glucose in HA-ObRb/Pomc-Cre/Leprdb/db mice was dependent of energy intake, eight weeks old female Leprdb/db mice were pair-fed (~30% intake reduction) to ad libitum fed HA-ObRb/Pomc-Cre/Leprdb/db littermates for three weeks (Figure 4F).”

  • The paper relies on this without support.

    The phenotype of HA-ObRb/Pomc-Cre/Leprdb/db mice is directly comparable to the phenotype resulting from arcuate-specific restoration of leptin receptors in Coppari et al. (2005).

    “Since these findings are directly comparable to the phenotype of our HA-ObRb/Pomc-Cre/Leprdb/db mice we conclude”

  • The paper relies on this without support.

    The phenotype resulting from unilateral restoration of endogenous leptin receptors in arcuate neurons is strikingly similar to that of HA-ObRb/Pomc-Cre/Leprdb/db mice.

    “results in a phenotype strikingly similar to that of our HA-ObRb/Pomc-Cre/Leprdb/db mice”
5 of 5

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?

  • Leptin signaling in POMC neurons plays an important role in leptin's ability to regulate glucose metabolism.

    “These data provide further evidence that leptin signaling in POMC neurons plays an important in leptin's ability to regulate glucose metabolism.”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [88]

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Authors
Huo, L., Gamber, K., Greeley, S., Silva, J., Huntoon, N., Leng, X.-H., & Bjørbæk, C.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Baylor College of Medicine (US)
Corresponding author
Bjørbæk, Christian
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2009-06
Volume
9
Issue
6
Pages
537-547
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2009.05.003
PMC
PMC2730605
OpenAlex
W2094751859
Semantic Scholar
95ea91daad2a28a34aff2806aa0df0859b58178d
Cited by
226
References
63
Citations by year
2026: 3 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 5 · 2021: 13 · 2020: 12 · 2019: 8 · 2018: 11 · 2017: 20 · 2016: 16 · 2015: 19 · 2014: 15 · 2013: 16 · 2012: 20
FWCI
9.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Diabetes Association
  • Richard and Susan Smith Family Foundation
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK65743, DK60673, P30DK046200, R01DK060673, R01DK065743, DK46200.)
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, POMC neurons, glucose homeostasis, locomotor activity, leptin receptor, db/db mice, obesity, diabetes mellitus, energy balance, energy intake, body weight
MeSH terms
Animals, Blood Glucose, Body Weight, Eating, Motor Activity, Neurons, Pro-Opiomelanocortin, Signal Transduction, Mice, Knockout, Leptin, Mice, Receptors, Leptin

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