ReviewThe many lives of leptin☆
Section snippets
Introduction: life as an adipostat
In 1994, Zhang et al. [86] published a paper which solved an old mystery. It had long been known from parabiosis studies that the blood from rats with obesity induced by forced feeding, electrical stimulation, or some genetic lesions contained a substance which reduced food intake and fat mass in their partners [23], [48], [69]. Using modern molecular biology tools, Zhang et al. identified this substance to be Ob protein, now more widely known as leptin. Leptin is secreted from adipose tissue
A background of peptide and protein transport across the BBB
Our laboratory had a long-standing interest in the question of whether peptides or proteins could cross the BBB at the time leptin was discovered. Despite the majority of opinion against the idea that peptides could not cross, a small group of researchers persevered throughout the 1980s, examining the question, developing new tools, and refining analyses. Our review in 1985 stated the evidence gathered to that time that supported the idea that peptides could cross the BBB [11] and was in direct
Blood to brain passage: the pathways available to leptin
Of the various pathways by which peptides and proteins cross the BBB, two had been considered for leptin: saturable transport and entry into the CNS by way of the CVOs. Our manuscript addressed both of these pathways.
Small, lipid soluble substances can enter the CNS from the blood by diffusing through the membranes which comprise the BBB [67]. Even some of the smaller peptides can enter enough to affect brain function [10], [13]. But our manuscript confirmed that leptin, which is about 1/4th
Summary: the role of the BBB in the lives of leptin
Leptin must cross the BBB to act at the arcuate nucleus. It does so because a saturable transport system exits at the vascular BBB and choroid plexus. Failure of this transporter is a major contributor to the development of leptin resistance in obesity. In humans and diet-induced obesity of outbred rodents, BBB resistance likely precedes resistance at the arcuate nucleus. BBB resistance is acquired and to some extent reversible. The BBB transporter for leptin is regulated by a number of
Acknowledgements
Supported by VA merit review and R01 NS41863 and R01 AA12743.
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Peripheral versus central insulin and leptin resistance: Role in metabolic disorders, cognition, and neuropsychiatric diseases
2022, NeuropharmacologyCitation Excerpt :Likewise, leptin resistance is characterized by reduced central and/or peripheral actions of leptin in the presence of adequate (or often elevated) levels. Leptin resistance can also occur at several different steps (Banks, 2004a; Sáinz et al., 2015; Wauman and Tavernier, 2011) including: 1) failure of circulating leptin to reach its targets in the brain, possibly due to defective transport across the BBB (Banks et al., 1999; Caro et al., 1996; Münzberg and Myers, 2005); 2) leptin receptor downregulation (Martin et al., 2000); or 3) a defect in the leptin signaling cascade and downstream effectors (Levin et al., 2004; Münzberg et al., 2005). Clinical data indicate that insulin and leptin resistance, alone or in combination, are components of a host of related metabolic disorders including diabetes/prediabetes and obesity.
Leptin resistance and hippocampal behavioral deficits
2017, Physiology and BehaviorCitation Excerpt :Indeed, these experimental models exhibit a variety of changes that may include insulin resistance, hyperglycemia, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, increases in pro-inflammatory cytokines and decreases in the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) [81]. Moreover, CNS leptin resistance involves both a decrease in leptin transport across the BBB and decreases in leptin receptor signaling [82,83]. As such, differentiating cause from consequence in the development of neurobehavioral deficits in metabolic disorders that involve peripheral endocrine abnormalities and CNS deficits represents a major obstacle in the development of strategies to effectively manage cognitive deficits and neuropsychiatric disorders in obesity, MetS and T2DM.
Leptin resistance elicits depressive-like behaviors in rats
2017, Brain, Behavior, and Immunity
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DOI of original article: 10.1016/0196-9781(96)00025-3.