HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms

White, Christy L.; Whittington, Amy; Barnes, Maria J.; Wang, Zhong; Bray, George A.; Morrison, Christopher D.

doi:10.1152/ajpendo.90513.2008

Cited by 124 publications

(81 citation statements)

References 44 publications

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“…The expression of PTP1B is induced in the hypothalamus of mice in response to high-fat feeding, and PTP1B deficiency in the brain results in decreased body weight and improved leptin sensitivity (16,17,19,50,51). However, the role(s) played by PTP1B in specific neurons that control energy balance remains unknown.…”

Section: Discussionmentioning

confidence: 99%

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

Banno¹,

Zimmer²,

Jonghe³

et al. 2010

J. Clin. Invest.

185

161

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Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuronspecific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b -/-mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2 -/-mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b -/-mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMCShp2 -/-mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and α-melanocyte-stimulating hormone (αMSH) peptide levels were markedly reduced in POMC-Shp2 -/-mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system. IntroductionObesity has become a major health concern worldwide (1). Currently there are few effective therapies for targeting obesity and its associated comorbidities in humans. The CNS has long been implicated in the control of energy balance, with the hypothalamus playing a key role as an integrator of metabolic information (reviewed in ref. 2). Thus, an important area of obesity research centers on understanding the neural signaling pathways that control energy balance.Within the hypothalamus, first-order neurons in the arcuate nucleus (ARC) respond to circulating adiposity signals, such as insulin and leptin, and project to second-order neurons in the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), and the lateral hypothalamus (LHA) to mediate effects on food intake and energy expenditure (3-7). Two distinct populations of first-order neurons synthesize either agouti-related protein (AgRP) or proopiomelanocortin (POMC) and mediate opposing effects on energy balance (4,8). The POMC precursor is cleaved into biologically active peptides, including α-melanocyte-stimulating hormone (αMSH), which binds to melanocortin-3 and -4 receptors on target second-order neurons (9). The adipocyte-secreted hormone leptin acts in the brain as a catabolic hormone to decrease appetite and increase energy expenditure via simultaneous suppression of AgRP neurons and stimulation of POMC neurons (4, 10, 11).The discovery of leptin init...

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Section: Discussionmentioning

confidence: 99%

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

Banno¹,

Zimmer²,

Jonghe³

et al. 2010

J. Clin. Invest.

185

161

View full text Add to dashboard Cite

show abstract

“…In the current experiment, the fact that the arcuate nucleus presents normal leptin-induced STAT3 phosphorylation during pregnancy suggests that transport into the brain is not significantly compromised. The underlying cause of the decrease in leptin-induced STAT3 phosphorylation in the VMN and PVN is unknown but could include decreases in the Ob-Rz, as has been demonstrated in the VMN in pregnant rats (Ladyman & Grattan 2005) or increases in inhibitory molecules of the JAK/STAT pathway such as SOCS or PTP1B, which have been seen in diet-induced (Bjorbaek et al 1998, Munzberg et al 2004, White et al 2009 or age-induced leptin-resistant animals (Peralta et al 2002, Morrison et al 2007.…”

Section: Discussionmentioning

confidence: 99%

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Ladyman¹,

Fieldwick²,

Grattan³

2012

Reproduction

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Hyperphagia during pregnancy, despite rising concentrations of the satiety hormone leptin, suggests that a state of leptin resistance develops. This study investigated the satiety response and hypothalamic responses to leptin during pregnancy in the mouse. Pregnant (day 13) and nonpregnant mice received an i.p. injection of either leptin or vehicle and then 24-h food intake was measured. Further groups of pregnant and nonpregnant mice were perfused 2 h after leptin or vehicle injections and brains were processed for pSTAT3 and pSTAT5 immunohistochemistry. Leptin treatment significantly decreased food intake in nonpregnant mice. In pregnant mice, however, leptin treatment did not suppress food intake, indicating a state of leptin resistance. In the arcuate nucleus, leptin treatment increased the number of cells positive for pSTAT3, a marker of leptin activity, to a similar degree in both nonpregnant and pregnant mice. In the ventromedial nucleus (VMN), the leptin-induced increase in pSTAT3-positive cell number was significantly reduced in pregnant mice compared to that in nonpregnant mice. In nonpregnant mice, leptin treatment had no effect on the number of pSTAT5-positive cells, suggesting that in this animal model, leptin does not act through STAT5. In pregnant mice, basal levels of pSTAT5 were higher than in nonpregnant mice, and leptin treatment led to a decrease in the number of pSTAT5-positive cells in the hypothalamus. Overall, these results demonstrate that during pregnancy in the mouse, a state of leptin resistance develops, and this is associated with a reduced sensitivity of the VMN to leptin.Reproduction (2012) 144 83-90

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“…However, for reasons that are not fully understood, obese individuals do not show diminished appetite and increased energy expenditure, as would be predicted based on their increased leptin levels (6,31). Likewise, in animal models, high-fat diet-induced hyperleptinemia aggravates weight gain and metabolic anomalies (32)(33)(34). In the face of these observations, researchers elaborated the concept of leptin resistance, which refers to the inability of obese individuals and high-fat-fed animals to respond to endogenous or exogenous leptin (35).…”

Section: Physiological Roles Of Rising and Falling Levels Of Leptinmentioning

confidence: 99%

Sixteen years and counting: an update on leptin in energy balance

Gautron¹,

Elmquist²

2011

J. Clin. Invest.

311

251

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Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. IntroductionThe nervous system regulates energy balance at the organismal level by constantly adjusting energy intake, expenditure, and storage. The influence of the nervous system over metabolic functions was first suggested at the beginning of the 20th century when excessive adiposity was associated with pituitary tumors and injury to the hypothalamus (1). However, it was not until the 1940s that selective surgical lesions of certain hypothalamic areas were found to result in extreme obesity or leanness in rats (2, 3). Over the last few decades, numerous discoveries substantially extended our understanding of the neural control of metabolism. However, it is safe to say that none were more important than the cloning of the ob gene by Friedman and colleagues in 1994 (4). The ob gene encodes the protein leptin, which is a hormone produced and secreted by the white adipose tissue, and consequently, its circulating levels are closely related to body fat mass (5, 6). Leptin deficiency in mice homozygous for a mutant ob gene (ob/ob mice) causes morbid obesity, diabetes, and various neuroendocrine anomalies, and leptin replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure (7-10). Several splice variants of the leptin receptor have been identified, and the "short forms" are widely expressed in multiple tissues (11). The "long form" of the leptin receptor encodes a protein with a longer cytoplasmic domain (OB-Rb) that is highly expressed in particular sites within the CNS (refs. 10, 12, and Table 1). The short forms of the leptin receptor are also present within the CNS (11), but OB-Rb is sufficient for leptin actions on metabolism (13,14). OB-Rb is a type 1 cytokine receptor, which stimulates the JAK/STAT3 pathway (15) and PI3K (16,17). Leptin induces transcriptional changes of several genes via the JAK/STAT3 pathway, and rapid changes in cellular activity and membrane potential may underlie the acute actions of leptin (18). While actions of this hormone in peripheral tissues have been identified, studies in genetically modified mice have demonstrated that leptin action only in the CNS is sufficient to regulate body weight, feeding, energy expenditure, and glucose metabolism (13,(19)(20)(21).Since leptin is clearly not the only metabolic signal acting on the brain, the range of its effects on behavior, metabolism, and endocrinology is trul...

show abstract

HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms

Cited by 124 publications

References 44 publications

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Sixteen years and counting: an update on leptin in energy balance

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