Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age

Morrison, Christopher D.; White, Christy L.; Wang, Zhong; Lee, Seung Yub; Lawrence, David S.; Cefalu, William T.; Zhang, Zhong Yin; Gettys, Thomas W.

doi:10.1210/en.2006-0672

Cited by 99 publications

(96 citation statements)

References 46 publications

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“…Similar results have been observed in several rodent models showing an age-dependent loss of leptin sensitivity (4,39,40). Furthermore, decreases or complete loss of leptin induced pSTAT3 response have been observed in aged rodents (6,7,27). This aspect of age-related emergence of leptin resistance is often overlooked in the literature.…”

Section: Discussionsupporting

confidence: 81%

“…S2B). However, the ability to assess a response to leptin in rodents using markers such as pSTAT3 diminishes in aged animals (6,7,27). These results indicate that obese Ift88 Δ/Δ mice have elevated leptin levels and display behavior consistent with hyperleptinemiaassociated leptin resistance.…”

Section: Resultsmentioning

confidence: 96%

“…This barrier phenomenon is known as leptin resistance, the precise mechanisms of which are unknown. Furthermore, age impacts leptin sensitivity, as older rodents are less responsive to the anorectic effects of leptin than younger rodents (4)(5)(6)(7). In the field of obesity research, one challenge becomes determining how individuals acquire leptin resistance and whether this is a primary cause of the obesity phenotype or simply a consequence.…”

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confidence: 99%

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Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

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

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Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 96%

mentioning

confidence: 99%

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Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

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

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“…Leptin resistance has been shown to develop in vagal afferent neurons in high-fat-fed rats (11), and aging is associated with peripheral and central metabolic leptin resistance that involves transporter saturation, defective intracellular signaling, and receptor downregulation (14,33,39). Leptin sensitivity for cardiovascular actions during aging, however, is unknown.…”

Section: Discussionmentioning

confidence: 99%

Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats

Arnold

Diz

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Arnold AC, Diz DI. Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats. Am J Physiol Heart Circ Physiol 307: H1539 -H1546, 2014. First published September 26, 2014; doi:10.1152/ajpheart.00282.2014.-The decline in cardiovagal baroreflex function that occurs with aging is accompanied by an increase in circulating leptin levels. Our previous studies showed that exogenous leptin impairs the baroreflex sensitivity for control of heart rate in younger rats, but the contribution of this hormone to baroreflex dysfunction during aging is unknown. Thus we assessed the effect of bilateral leptin microinjection (500 fmol/60 nl) within the solitary tract nucleus (NTS) on the baroreflex sensitivity in older (66 Ϯ 2 wk of age) urethane/chloralose anesthetized SpragueDawley rats with elevated circulating leptin levels. In contrast to the 63% reduction observed in younger rats, leptin did not alter the baroreflex sensitivity for bradycardia evoked by phenylephrine in older rats (0.76 Ϯ 0.19 baseline vs. 0.71 Ϯ 0.15 ms/mmHg after leptin; P ϭ 0.806). We hypothesized that this loss of sensitivity reflected endogenous suppression of the baroreflex by elevated leptin, rather than cardiovascular resistance to the peptide. Indeed, NTS administration of a leptin receptor antagonist (75 pmol/120 nl) improved the baroreflex sensitivity for bradycardia in older rats (0.73 Ϯ 0.13 baseline vs. 1.19 Ϯ 0.26 at 10 min vs. 1.87 Ϯ 0.32 at 60 min vs. 1.22 Ϯ 0.54 ms/mmHg at 120 min; P ϭ 0.002), with no effect in younger rats. There was no effect of the leptin antagonist on the baroreflex sensitivity for tachycardia, responses to cardiac vagal chemosensitive fiber activation, or resting hemodynamics in older rats. These findings suggest that the actions of endogenous leptin within the NTS, either produced locally or derived from the circulation, contribute to baroreflex suppression during aging. autonomic; aging; arterial baroreflex; leptin THE ARTERIAL BARORECEPTOR reflex is critically involved in short-term regulation of blood pressure through modulation of central autonomic pathways that control sympathetic and parasympathetic outflow to peripheral cardiovascular organs. During aging, there is impairment of the baroreflex sensitivity (BRS) for control of heart rate (HR) (13, 15, 32), a marker of parasympathetic tone mediated at the level of the solitary tract nucleus (NTS) in the dorsal medulla (2), due to changes in central neuronal and peripheral vascular function. Importantly, baroreflex dysfunction is permissive to chronic sympathetic activation to increase blood pressure and its variability and is an independent risk factor for cardiovascular morbidity and mortality (25,42). The precise mechanisms involved in agerelated baroreflex impairments, however, are not fully understood. The identification of hormones or other factors that modulate autonomic brainstem regions, such as the NTS, may therefore improve our understanding of the decline in baroreflex function that occurs with aging.Aging is...

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“…Thus, in aged rats a decline in STAT3 activation is observed that is linked to a decrease in leptin responsiveness [19]. Conversely, elevations in SOCS-3 and PTP1B (protein tyrosine phosphatase 1B) levels, which limit leptin receptor signal transduction, are evident in aged animals [20,21]. Recent studies have identified links between age-related alterations in leptin levels and cognitive performance [22]; however, the cellular basis for the age-dependent alterations in the cognitive enhancing effects of leptin are unclear.…”

Section: Introductionmentioning

confidence: 98%

Leptin regulation of hippocampal synaptic function in health and disease

Irving

Harvey

2014

Phil. Trans. R. Soc. B

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The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.

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Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age

Cited by 99 publications

References 46 publications

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats

Leptin regulation of hippocampal synaptic function in health and disease

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