The DOI matches its Crossref record; 61 of the 63 references it cites were found in a registry or an index; 3 of the 58 sources its claims cite were checked for support.
Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons
Open accessAbstract
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.
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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.
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Claims the paper makes
48 Own result · 40 Not checked yet · 23 Own interpretation · 3 Own method · 2 No basis given · 1 Supported · 1 Supported so far · 1 Partly supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, deletion of leptin-receptors from AgRP neurons results in a modest reduction in activity (van de Wall et al., 2007)”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
What the sources say
- Supportedcites van de Wall et al., 2007 source
Figure 4C, reproduced in the section on selective LEPR ablation (page unavailable), reports significantly reduced locomotor activity in male mice lacking leptin receptors in AgRP neurons during the dark phase. The discussion also describes these mice as having reduced locomotor activity; it does not quantify the reduction as “modest.” (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Abstract
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- Also stated in: § Leptin signaling in POMC neurons of Leprdb/db mice reduces body weight and food intake · plain
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Effects of leptin signaling in POMC neurons on neuropeptides
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
What the sources say
- Not checked yetcites Munzberg et al., 2004 source
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Normalization of glucose by ObRb in POMC neurons in Leprdb/db mice
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“As shown in Figure 4E, this food restriction did not reduce hyperglycemia in Leprdb/db mice.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Normalization of glucose by ObRb in POMC neurons in Leprdb/db mice
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Islets from HA- ObRb/Pomc-Cre/Leprdb/db mice appeared structurally intact.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin receptors in POMC neurons of Leprdb/db mice increases islet mass
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In 12 weeks old fasted HA-ObRb/pomc-Cre/Leprdb/db mice, blood glucose levels were markedly reduced as compared to Leprdb/db mice (Supplemental Figure 2A), despite only a slight decrease in weight (Supplemental Figure 2B).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Normalization of glucose by ObRb in POMC neurons in Leprdb/db mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fat mass and circulating leptin levels tended towards a modest decrease in HA-ObRb/Pomc-Cre/Leprdb/db mice versus Leprdb/db mice (Figure 3E and 3F, Table 1).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin signaling in POMC neurons of Leprdb/db mice reduces body weight and food intake
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found a 50% decreased level of P-STAT3 in HA-ObRb/Pomc-Cre/Leprdb/db mice relative to control mice (Supplemental Figure 1).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plain- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 16
- It may state two separate claims as one. 35
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“and inhibit hepatic glucose production (Pocai et al., 2005; van den Hoek et al., 2008).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
- Supportedcites Pocai et al., 2005 source
The section on hepatic insulin action in overfed rats reports that intracerebroventricular leptin reduced glucose production during the insulin clamp (Fig. 1E). The effect was observed in overfed rats; the paper reports no change in glucose production in standard-diet rats. (LLM, conf=0.92)
- Not checked yetcites van den Hoek et al., 2008 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Long-term impairment of central melanocortin receptor action in mice results in marked obesity, hyperinsulinemia, and late-onset hyperglycemia (Huszar et al., 1997).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
- Partly supportedcites Huszar et al., 1997 sourceExperimental — accuracy not yet measured
The body-weight and serum-insulin results report marked obesity and hyperinsulinemia in MC4-R-deficient mice of both sexes. The serum-glucose results report later-onset hyperglycemia in males, first evident in homozygous males at 10–14 weeks, but say glucose was essentially unchanged in females. The claim omits that sex-specific limit. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Effects of leptin signaling in POMC neurons on neuropeptides
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin signaling in POMC neurons of Leprdb/db mice reduces body weight and food intake
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Normalization of glucose by ObRb in POMC neurons in Leprdb/db mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin receptors in POMC neurons increases activity
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Body length (Table 1) and lean mass was not different among these groups (not shown).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin signaling in POMC neurons of Leprdb/db mice reduces body weight and food intake
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin signaling in POMC neurons of Leprdb/db mice reduces body weight and food intake
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Normalization of glucose by ObRb in POMC neurons in Leprdb/db mice
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The HA-tag did not interfere with STAT3 activation by ObRb in transfected cells (not shown).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin receptors in POMC neurons of Leprdb/db mice increases islet mass
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Generation of mice expressing leptin receptors in POMC neurons
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
- Not checked yetcites Obici et al., 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Insulin resistance is present before the onset of obesity in melanocortin-4-receptor deficient mice (Fan et al., 2000).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
- Not checked yetcites Fan et al., 2000 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
What the sources say
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In the paper
“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)”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
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“AgRP is an endogenous melanocortin receptor antagonist that potently stimulates feeding (Ollmann et al., 1997).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Introduction
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- Not checked yetcites Ollmann et al., 1997 source
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin receptors in POMC neurons increases activity
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- Not checked yetcites Coppari et al., 2005 source
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In the paper
“In contrast, our studies demonstrate that leptin receptor signaling in POMC neurons is sufficient to exert remarkable control of serum glucose concentrations and locomotion.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Leptin receptors in POMC neurons of Leprdb/db mice increases islet mass
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In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Results > Normalization of glucose by ObRb in POMC neurons in Leprdb/db mice
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In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Abstract
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- Also stated in: § Discussion · plain
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
What the sources say
- Not checked yetcites Hwa et al., 1997
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In the paper
“we conclude that arcuate POMC neurons, but not NTS POMC neurons, are responsible for mediating those effects of leptin.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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).
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The housekeeping gene cyclophilin was used for normalization.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Experimental Procedures > Hypothalamic Neuropeptide mRNA
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“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
What the sources say
- Not checked yetcites Musi and Goodyear, 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“our data show that leptin signaling specifically in hypothalamic POMC neurons is sufficient to correct diabetes and greatly increase locomotion in Leprdb/db mice”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“Exercise training increases insulin-sensitivity and improves glucose homeostasis (Hespel et al., 1996; Ryder et al., 2001).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
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In the paper
“Animal care and procedures were approved by the Institutional Animal Care and Use Committee at Beth Israel Deaconess Medical Center.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Experimental Procedures > Animal Care
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a possible role of these cells in mediating some of the phenotypic changes in HA-ObRb/Pomc-Cre/Leprdb/db animals cannot be excluded.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
What the sources say
- Not checked yetcites Dhillon et al., 2006 source
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In the paper
“In addition, central administration of melanocortin receptor agonists is sufficient to activate muscle AMPK phosphorylation in mice (Tanaka et al., 2007).”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Discussion
What the sources say
- Not checked yetcites Tanaka et al., 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons > Experimental Procedures > Generation of HA-ObRb/Pomc-Cre/Leprdb/db Mice
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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”
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?
In the citing paper
“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]
Citations
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Cited by
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Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism
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InfluentialLeptin and the Central Nervous System Control of Glucose Metabolism
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“When POMC-cre was used to drive recombination of mutated LepR and thus restore LepR function selectively within POMC neurons, there was a complete reversal of hyperglycemia and improved insulin sensitivity [84,85].”
PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
Banno, R., Zimmer, D., De Jonghe, B. C., Atienza, M., Rak, K., Yang, W., & Bence, K. K. (2010) · Journal of Clinical Investigation · doi:10.1172/jci39620 · Cited by 214
POMC neuronal heterogeneity in energy balance and beyond: an integrated view
Quarta, C., Claret, M., Zeltser, L. M., Williams, K. W., Yeo, G. S. H., Tschöp, M. H., Diano, S., Brüning, J. C., & Cota, D. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00345-3 · Cited by 194
Hypothalamic-autonomic control of energy homeostasis
Seoane‐Collazo, P., Fernø, J., González, F., Diéguez, C., Leis, R., Nogueiras, R., & López, M. (2015) · Endocrine · doi:10.1007/s12020-015-0658-y · Cited by 189
Leptin receptor signaling: pathways to leptin resistance
Wauman, J. (2011) · Frontiers in bioscience · doi:10.2741/3885 · Cited by 182
“and a modest reduction in body weight in db/db mice, but remarkably completely normalized blood glucose levels and locomotor activity (44).”
The Leptin Receptor Complex: Heavier Than Expected?
Wauman, J., Zabeau, L., & Tavernier, J. H. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00030 · Cited by 185
Minireview: CNS Mechanisms of Leptin Action
Flak, J. N., & Myers, M. G. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1232 · Cited by 179
Park, H.-K., & Ahima, R. S. (2014) · F1000Prime Reports · doi:10.12703/p6-73 · Cited by 171
“Moreover, selective expression of LepRb in the POMC neurons dramatically improves glucose levels in db/db mice [39,40].”
POMC Neurons: From Birth to Death
Toda, C., Santoro, A. N., Kim, J. D., & Diano, S. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034110 · Cited by 175
Hypothalamic mechanisms in cachexia
Grossberg, A. J., Scarlett, J. M., & Marks, D. L. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.03.011 · Cited by 162
“Recently, intact leptin signaling in both POMC and AgRP neurons has been associated with controlling locomotor activity to the extent that it can significantly alter total energy homeostasis [196,197].”
The role of leptin in health and disease
Ramos-Lobo, A. M., & Donato, J. (2017) · Temperature · doi:10.1080/23328940.2017.1327003 · Cited by 172
“Leptin signaling only in the ARH or specifically in POMC neurons can partially rescue the hypoactivity displayed by LepR-deficient mice.(64,110,166) NPY/AgRP neurons also regulate locomotor activity since LepR ablation only in these cells causes decreased ambulatory activity compared with wild-type mice.”
Al‐Qassab, H., Smith, M. A., Irvine, E. E., Guillermet‐Guibert, J., Claret, M., Choudhury, A. I., Selman, C., Piipari, K., Clements, M., Lingard, S. J., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.09.008 · Cited by 165
Central nervous system regulation of organismal energy and glucose homeostasis
Myers, M. G., Affinati, A. H., Richardson, N. E., & Schwartz, M. W. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00408-5 · Cited by 165
Role of leptin in the pancreatic β-cell: effects and signaling pathways
Marroquí, L., González, A., Ñeco, P., Caballero‐Garrido, E., Vieira, E. C., Ripoll, C., Nadal, Á., & Quesada, I. (2012) · Journal of Molecular Endocrinology · doi:10.1530/jme-12-0025 · Cited by 168
Hypothalamic control of energy metabolism via the autonomic nervous system
Kalsbeek, A., Bruinstroop, E., Yi, C., Klieverik, L. P., la Fleur, S. E., & Fliers, E. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05800.x · Cited by 152
Lee, E., Jung, D. Y., Kim, J. H., Patel, P. R., Hu, X., Lee, Y., Azuma, Y., Wang, H.-F., Tsitsilianos, N., Shafiq, U., et al. (2015) · The FASEB Journal · doi:10.1096/fj.14-268300 · Cited by 147
“Recent studies have shown that leptin affects locomotor activity and energy expenditure in addition to its wellestablished effect on feeding behavior (21, 22).”
Farr, O. M., Tsoukas, M. A., & Mantzoros, C. S. (2014) · Metabolism · doi:10.1016/j.metabol.2014.07.004 · Cited by 153
Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects
Cai, H., Dong, L., & Liu, F. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.11.011 · Cited by 152
“Although decreased circulating leptin levels could partially account for the reduced physical activity observed in raptor-null mice [89,90], it is likely that the levels of other unidentified adipokines may also be changed due to inactivation of mTORC1 signaling in fat, through which adipose tissue communicates with o…”
Circadian Rhythms of the Hypothalamus: From Function to Physiology
Drunen, R. V., & Eckel‐Mahan, K. L. (2021) · Clocks & Sleep · doi:10.3390/clockssleep3010012 · Cited by 146
“Adipose-derived leptin activates NPY/AgRP and POMC neurons to suppress food intake and stimulate energy expenditure [225].”
Central nervous control of energy and glucose balance: focus on the central melanocortin system
Xu, Y., Elmquist, J. K., & Fukuda, M. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06248.x · Cited by 135
Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update
Tiwari, P. (2015) · Journal of Diabetes Research · doi:10.1155/2015/340838 · Cited by 140
“Leptins also regulate glucose homeostasis through the activation of leptin receptors (LEPRs) [89–92].”
Leptin Engages a Hypothalamic Neurocircuitry to Permit Survival in the Absence of Insulin
Fujikawa, T., Berglund, E. D., Patel, V. R., Ramadori, G., Vianna, C. R., Vong, L., Thorel, F., Chera, S., Herrera, P. L., Lowell, B. B., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.004 · Cited by 135
“Because hypothalamic POMC and steroidogenic factor 1 (SF1) neurons have been shown to regulate glucose metabolism in insulin-intact mammals (Berglund et al., 2012; Huo et al., 2009; Ramadori et al., 2011), we directly tested whether LEPRs in POMC or SF1 neurons (POMC or SF1, respectively) are required for the effects…”
Leshan, R. L., Opland, D. M., Louis, G. W., Leinninger, G. M., Patterson, C. M., Rhodes, C. J., Münzberg, H., & Myers, M. G. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1001-10.2010 · Cited by 127
“…including the role of leptin in regulating LepRb/pro-opiomelanocortin (POMC)-expressing neurons and their opposing LepRb/agouti-related protein (AgRP)/neuropeptide Y-expressing neurons in the ARC (Elmquist et al., 2005; Morton et al., 2006; Berthoud, 2007; Gao and Horvath, 2007; Huo et al., 2009).”
Neuronal regulation of homeostasis by nutrient sensing
Lam, T. K. T. (2010) · Nature Medicine · doi:10.1038/nm0410-392 · Cited by 125
Caron, A., Lemko, H. M. D., Castorena, C. M., Fujikawa, T., Lee, S., Lord, C. C., Ahmed, N. I., Lee, C. E., Holland, W. L., Liu, C., et al. (2018) · eLife · doi:10.7554/elife.33710 · Cited by 122
“DOI: https://doi.org/10.7554/eLife.33710 1 of 18 observations that prenatal manipulations of LEPR-expressing POMC neurons mildly affect body weight (Münzberg et al., 2003; Balthasar et al., 2004; Huo et al., 2009; Berglund et al., 2012; Huang et al., 2012; Mercer et al., 2013).”
InfluentialPadilla, S. L., Reef, D. K., & Zeltser, L. M. (2011) · Endocrinology · doi:10.1210/en.2011-1665 · Cited by 120
Ring, L. E., & Zeltser, L. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41985 · Cited by 115
Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons
Fernandes, M. F., Matthys, D., Hryhorczuk, C., Sharma, S., Mogra, S., Alquier, T., & Fulton, S. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.003 · Cited by 119
“, 2005) or proopiomelanocortin neurons (Huo et al., 2009), underscoring the role of the hypothalamus in the actions of leptin to stimulate locomotor behavior.”
Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes
Mountjoy, K. G. (2010) · Biochemical Journal · doi:10.1042/bj20091957 · Cited by 110
Adipose tissue and reproductive health
Mathew, H., Castracane, V. D., & Mantzoros, C. S. (2017) · Metabolism · doi:10.1016/j.metabol.2017.11.006 · Cited by 109
Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling
Hu, H., Kong, D., Byun, K. H., Ye, C., Koda, S., Lee, D. H., Oh, B., Lee, S. W., Lee, B., Zabolotny, J. M., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3207 · Cited by 106
Self-citationPedroso, J. A. B., Buonfiglio, D. D. C., Cardinali, L. I., Furigo, I. C., Ramos-Lobo, A. M., Tirapegui, J., Elias, C. F., & Donato, J. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.06.001 · Cited by 106
Williams, K. W., Scott, M. M., & Elmquist, J. K. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.11.042 · Cited by 96
“Christain Bjorbaek's group recently investigated whether overexpression of LepRb in POMC cells alone was sufficient to regulate energy and glucose homeostasis (Huo et al., 2009).”
AMPK and the neuroendocrine regulation of appetite and energy expenditure
Stark, R., Ashley, S. E., & Andrews, Z. B. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.012 · Cited by 94
“, 2009), but a strong effect on whole body glucose metabolism (Huo et al., 2009).”
Gamber, K. M., Huo, L., Ha, S., Hairston, J. E., Greeley, S., & Bjørbæk, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030485 · Cited by 96
Self-citationRegulatory role of leptin in glucose and lipid metabolism in skeletal muscle
Minokoshi, Y., Toda, C., & Okamoto, S. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105573 · Cited by 97
Hyperinsulinemia Precedes Insulin Resistance in Mice Lacking Pancreatic β-Cell Leptin Signaling
Gray, S. L., Donald, C., Jetha, A., Covey, S. D., & Kieffer, T. J. (2010) · Endocrinology · doi:10.1210/en.2010-0102 · Cited by 94
Shpakov, A. O., Derkach, K. V., & Berstein, L. M. (2015) · Future Science OA · doi:10.4155/fso.15.23 · Cited by 93
Central Leptin Receptor Action and Resistance in Obesity
Bjørbæk, C. (2009) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e3181bb0d49 · Cited by 88
“Future studies are needed to explain how deletion of leptin receptors in POMC of normal mice does not lead to significant impairments in glucose balance(22) but that reexpression of receptors in POMC neurons of diabetic Lepr mice leads to this dramatic correction of blood glucose levels.(24) Regardless, POMC neurons a…”
InfluentialSelf-citationTRAP-seq defines markers for novel populations of hypothalamic and brainstem LepRb neurons
Allison, M. B., Patterson, C. M., Krashes, M. J., Lowell, B. B., Myers, M. G., & Olson, D. P. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.01.012 · Cited by 81
Contrasting Effects of Leptin on Food Anticipatory and Total Locomotor Activity
Ribeiro, A. C. D. M., Ceccarini, G., Dupré, C., Friedman, J. M., Pfaff, D. W., & Mark, A. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023364 · Cited by 81
“mice with loss of leptin receptor function, restoration of LRb only in pro-opiomelanocortin (POMC) neurons virtually normalizes locomotor activity with only modest decreases in body weight”
Morton, G. J., Kaiyala, K. J., Fisher, J. D., Ogimoto, K., Schwartz, M. W., & Wisse, B. E. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00546.2010 · Cited by 81
The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis
Coll, A. P., & Yeo, G. S. H. (2013) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2013.09.010 · Cited by 85
“Several groups have demonstrated in db/db animals that selective re-expression of the leptin receptor in just one side of the arcuate or within arcuate POMC neurons produces robust improvements in the glucose/insulin profile, while body weight is only modestly reduced [17–18] Similar results have been reported by Berg…”
Androgen Excess in Pancreatic β Cells and Neurons Predisposes Female Mice to Type 2 Diabetes
Navarro, G., Allard, C., Morford, J. J., Xu, W., Liu, S., Molinas, A. J. R., Butcher, S. M., Fine, N. H. F., Blandino-Rosano, M., Sure, V. N., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.98607 · Cited by 80
“sensitivity (20), and reexpression of leptin receptors exclusively in POMC neurons of leptin receptor–deficient mice normalizes blood glucose independently of obesity (21).”
Role of POMC and AgRP neuronal activities on glycaemia in mice
Üner, A. G., Keçik, O., Quaresma, P. G. F., de Araújo, T. M., Lee, H., Li, W., Kim, H. J., Chung, M., Bjørbæk, C., & Kim, Y. (2019) · Scientific Reports · doi:10.1038/s41598-019-49295-7 · Cited by 73
Self-citationDisruption of Hepatic Leptin Signaling Protects Mice From Age- and Diet-Related Glucose Intolerance
Huynh, F. K., Levi, J., Denroche, H. C., Gray, S. L., Voshol, P. J., Neumann, U. H., Speck, M., Chua, S. C., Covey, S. D., & Kieffer, T. J. (2010) · Diabetes · doi:10.2337/db10-0074 · Cited by 79
“3 glucose metabolism result from activation of central leptin signaling pathways (11-13) that regulate hepatic glucose flux (12, 13).”
Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?
Genchi, V. A., D’Oria, R., Palma, G., Caccioppoli, C., Cignarelli, A., Natalicchio, A., Laviola, L., Giorgino, F., & Perrini, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126445 · Cited by 83
Cyclic AMP sensor EPAC proteins and energy homeostasis
Almahariq, M. F., Mei, F. C., & Cheng, X. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.10.004 · Cited by 73
“For instance, restoration of OB-Rb expression in OB-Rb-deficient mice, and in particular in POMC neurons, was sufficient to normalize blood glucose levels while having little impact on body weight [63, 64].”
The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis
Guan, X. (2014) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00096.2014 · Cited by 70
“Moreover, leptin 248 signaling in POMC neurons is sufficient to correct diabetes in Lepr mice(58), while insulin 249 receptor (InsR) activation in POMC neurons promotes HGP (76; 96), pointing to the central 250 control of POMC neurons in glucose homeostasis.”
Neuroendocrine integration of nutritional signals on reproduction
Evans, M. C., & Anderson, G. M. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0212 · Cited by 66
Schaab, M., Kausch, H., Klammt, J., Nowicki, M., Anderegg, U., Gebhardt, R., Rose‐John, S., Scheller, J., Thiery, J., & Kratzsch, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034787 · Cited by 68
Neuroinflammatory and autonomic mechanisms in diabetes and hypertension
Han, C., Rice, M. W., & Cai, D. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00012.2016 · Cited by 66
Toda, C., Shiuchi, T., Kageyama, H., Okamoto, S., Coutinho, E. A., Sato, T., Okamatsu‐Ogura, Y., Yokota, S., Takagi, K., Tang, L., et al. (2013) · Diabetes · doi:10.2337/db12-1629 · Cited by 62
“Restoration of expression of the Ob-Rb receptor for leptin in proopiomelanocortin (POMC) neurons of db/db mice (which lack Ob-Rb) normalizes blood glucose concentration (12,13).”
Gonçalves, G. H. M., Li, W., Garcia, A. V. C.-G., Figueiredo, M. S., & Bjørbæk, C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.010 · Cited by 64
Self-citationThe Role of the Melanocortin System in Metabolic Disease: New Developments and Advances
Hill, J. W., & Faulkner, L. D. (2016) · Neuroendocrinology · doi:10.1159/000450649 · Cited by 57
The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis
Shi, H., Sorrell, J. E., Clegg, D. J., Woods, S. C., & Seeley, R. J. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.02.018 · Cited by 55
Sex differences in the effects of androgens acting in the central nervous system on metabolism
Morford, J. J., & Mauvais‐Jarvis, F. (2016) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2016.18.4/fmauvais · Cited by 53
Gerstenberg, M. K., Salinas, C. B. G., Rehfeld, J. F., Secher, A., Raun, K., & Wulff, B. S. (2018) · Neuropeptides · doi:10.1016/j.npep.2018.11.004 · Cited by 52
“The energy homeostasis is tightly regulated by the central nervous system that integrates signals from the peripheral and central brain regions (Schwartz, 2006; Huo et al., 2009; Sohn et al., 2013).”
Hormonal Gut–Brain Signaling for the Treatment of Obesity
Roh, E., & Choi, K. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043384 · Cited by 61
“In addition, leptin action in POMC neurons stimulates locomotion and prevents diabetes in morbidly obese, diabetic, and severely hypoactive leptin receptor-deficient db/db mice [44].”
Lucas, N., Legrand, R., Deroissart, C., Dominique, M., Azhar, S., Solliec, M.-A. L., Léon, F., do-Rego, J.-C., Déchelotte, P., Fetissov, S. O., et al. (2019) · Microorganisms · doi:10.3390/microorganisms8010035 · Cited by 49
A Treasure Trove of Hypothalamic Neurocircuitries Governing Body Weight Homeostasis
Vianna, C. R., & Coppari, R. (2010) · Endocrinology · doi:10.1210/en.2010-0778 · Cited by 51
Goel, M., Mittal, A., Jain, V. R., Bharadwaj, A., Modi, S., Ahuja, G., Jain, A., & Kumar, K. (2024) · Annals of Neurosciences · doi:10.1177/09727531241255492 · Cited by 68
“16 Hypothalamic activity is also known to be modulated by external temperature and to trigger responses such as shivering and sweating to regulate body temperature.”
Kang, K. S., Yahashi, S., & Matsuda, K. (2011) · Peptides · doi:10.1016/j.peptides.2011.05.006 · Cited by 47
Central signalling cross‐talk between insulin and leptin in glucose and energy homeostasis
Boucsein, A., Kamstra, K., & Tups, A. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12944 · Cited by 48
Leptin, diabetes, and the brain
Morton, G. J., & Meek, T. H. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105568 · Cited by 47
Melanocortin control of energy balance: evidence from rodent models
Jonghe, B. C. D., Hayes, M. R., & Bence, K. K. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0707-5 · Cited by 50
“This study, as well as several follow-up studies, highlight both the important contribution of POMC- and AgRP- neuron leptin signaling to overall energy balance, and the need to consider possible melanocortin receptorindependent effects of leptin [58-63].”
Ire1α in Pomc Neurons Is Required for Thermogenesis and Glycemia
Yao, T. S., Deng, Z., Gao, Y., Sun, J. M., Kong, X., Huang, Y., He, Z., Xu, Y., Chang, Y., Yu, K.-J., et al. (2016) · Diabetes · doi:10.2337/db16-0533 · Cited by 46
“Notably, these responses are phenotypic signatures of impaired leptin action within Pomc neurons (25-28).”
Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
Rathjen, T., Yan, X., Kononenko, N. L., Ku, M., Song, K., Ferrarese, L., Tarallo, V., Puchkov, D., Kochlamazashvili, G., Brachs, S., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4590 · Cited by 45
Should I Lay or Should I Grow: Photoperiodic Versus Metabolic Cues in Chickens
Hanlon, C., Ramachandran, R., Zuidhof, M. J., & Bédécarrats, G. Y. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00707 · Cited by 48
Li, X., Wu, X., Camacho, R. C., Schwartz, G. J., & LeRoith, D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017058 · Cited by 45
“The effect of ICV leptin on locomotor activity in the MKR mice contrasts the effect seen in other mouse models [13] and maybe specific to the MKR mice.”
Mitchell, S. E., Delville, C., Konstantopedos, P., Derous, D., Green, C. L., Wang, Y., Han, J. J., Promislow, D., Douglas, A., Chen, L., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.8158 · Cited by 44
“Leptin and insulin convey energy availability signals to the hypothalamus, a key site for the regulation of energy balance [56-58].”
The impact of androgen actions in neurons on metabolic health and disease
Morford, J. J., Wu, S., & Mauvais‐Jarvis, F. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.09.001 · Cited by 45
“POMC neurons expressing insulin and leptin receptors are also involved in hepatic insulin sensitivity (Berglund et al., 2012; Hill et al., 2010; Huo et al., 2009).”
Møller, C. L., Raun, K., Jacobsen, M. L., Pedersen, T. Å., Holst, B., Conde‐Frieboes, K. W., & Wulff, B. S. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.03.010 · Cited by 43
“Besides the effect on satiety and energy expenditure, the melanocortin system is believed to influence insulin release and insulin sensitivity (Fan et al. 2000; Huo et al. 2009).”
Pleiotropic Actions of the Incretin Hormones
McIntosh, C. H. S., Widenmaier, S. B., & Kim, S. (2010) · Vitamins and hormones · doi:10.1016/b978-0-12-381517-0.00002-3 · Cited by 42
ROCK1 in AgRP Neurons Regulates Energy Expenditure and Locomotor Activity in Male Mice
Hu, H., Lee, S., Ye, C., Sousa‐Lima, I., Oh, B., Lowell, B. B., Zabolotny, J. M., & Kim, Y. (2013) · Endocrinology · doi:10.1210/en.2013-1343 · Cited by 41
Central Leptin Regulation of Obesity and Fertility
Tong, Q., & Xu, Y. (2012) · Current Obesity Reports · doi:10.1007/s13679-012-0025-8 · Cited by 39
“This possibility appears not to be the case for POMC neurons since re-expression of LepRb selectively in POMC neurons, under which condition no developmental compensation will occur, produces little effects on body weight while largely restores euglycemia in db/db mice [19, 20].”
Melanocortin-3 Receptors and Metabolic Homeostasis
Begriche, K., Clemence, G., McDonald, P. H., & Butler, A. A. (2013) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-386933-3.00004-2 · Cited by 42
A critical update on the l eptin‐melanocortin system
Lavoie, O., Michael, N. J., & Caron, A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15765 · Cited by 43
“Selective re- expression of Lepr- b in POMC cells of db/db mice completely normalized blood glucose levels and partially restored blood insulin levels independently of food intake and body weight (Huo et al., 2009).”
Kaiyala, K. J., Morton, G. J., Thaler, J. P., Meek, T. H., Tylee, T. S., Ogimoto, K., & Wisse, B. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041473 · Cited by 37
Ibars, M., Aragonès, G., Ardid‐Ruiz, A., Gibert‐Ramos, A., Arola‐Arnal, A., Suárez, M., & Bladé, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-31855-y · Cited by 43
Neuroanatomical determinants of the sympathetic nerve responses evoked by leptin
Harlan, S. M., & Rahmouni, K. (2012) · Clinical Autonomic Research · doi:10.1007/s10286-012-0168-4 · Cited by 39
Ha, S., Baver, S. B., Huo, L., Gata, A., Hairston, J. E., Huntoon, N., Li, W., Zhang, T., Benecchi, E. J., Ericsson, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077622 · Cited by 38
“Leprdb/db;Pomc-cre;HA-Leprb flox and Leprdb/db;Agrp-ires-cre;HA-Leprb flox mice that selectively express HA-LepRb in POMC or AgRP neurons respectively, were generated by crossing the appropriate cre/lox lines with Leprdb/+ mice, as we have described previously [38].”
InfluentialSelf-citationZhang, X., Yang, R., Jia, Y., Cai, D., Zhou, B., Qu, X., Han, H., Xu, L., Wang, L., Yao, Y., et al. (2013) · Diabetes · doi:10.2337/db13-1221 · Cited by 38
“The expression of POMC in hypothalamus is facilitated by leptin, the fat-derived satiety signal, through OBRb (the long-form leptin receptor) signaling pathway to inhibit appetite of animals (10).”
Metadata
- 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
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 9
- Issue
- 6
- Pages
- 537-547
- ISSN
- 1550-4131 (ISSN-L)
- 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
- bronze
- doi.org
- 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 › Endocrinology, Diabetes and Metabolism › 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
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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