Brain Behavior and Immunity

评语： 

肥胖相关的代谢疾病和焦虑抑郁等情绪疾病的共病率非常高，治疗抑郁和焦虑的药物也通常会引起肥胖的代谢表型，因此解析代谢和焦虑的共病机制并找到有效的治疗方法至关重要。本研究聚焦于HFD引发的肥胖和焦虑，作者拓展了PEA除治疗代谢表型之外，对焦虑的改善作用。作者通过大脑多个脑区的炎症状态和血脑屏障的完整性揭示了PEA干预肥胖性焦虑的神经免疫机制，并通过体外细胞培养探究其分子机制。

关键词： 

high-fat diet; Palmitoylethanolamide; hypothalamic; amygdala; hippocampus; anxiety

文章链接DOI： 

https://linkinghub.elsevier.com/retrieve/pii/S0889-1591(22)00037-X

Abstract

High-fat diet (HFD) consumption leads to obesity and a chronic state of low-grade inflammation, named metainflammation. Notably, metainflammation contributes to neuroinflammation due to the increased levels of circulating free fatty acids and cytokines. It indicates a strict interplay between peripheral and central counterparts in the pathogenic mechanisms of obesity-related mood disorders. In this context, the impairment of internal hypothalamic circuitry runs in tandem with the alteration of other brain areas associated with emotional processing (i.e., hippocampus and amygdala). Palmitoylethanolamide (PEA), an endogenous lipid mediator belonging to the N-acylethanolamines family, has been extensively studied for its pleiotropic effects both at central and peripheral level. Our study aimed to elucidate PEA capability in limiting obesity-induced anxiety-like behavior and neuroinflammation-related features in an experimental model of HFD-fed obese mice. PEA treatment promoted an improvement in anxiety-like behavior of obese mice and the systemic inflammation, reducing serum pro-inflammatory mediators (i.e., TNF-α, IL-1β, MCP-1, LPS). In the amygdala, PEA increased dopamine turnover, as well as GABA levels. PEA also counteracted the overactivation of HPA axis, reducing the expression of hypothalamic corticotropin-releasing hormone and its type 1 receptor. Moreover, PEA attenuated the immunoreactivity of Iba-1 and GFAP and reduced pro-inflammatory pathways and cytokine production in both the hypothalamus and hippocampus. This finding, together with the reduced transcription of mast cell markers (chymase 1 and tryptase β2) in the hippocampus, indicated the weakening of immune cell activation underlying the neuroprotective effect of PEA. Obesity-driven neuroinflammation was also associated with the disruption of blood-brain barrier (BBB) in the hippocampus. PEA limited the albumin extravasation and restored tight junction transcription modified by HFD. To gain mechanistic insight, we designed an in vitro model of metabolic injury using human neuroblastoma SH-SY5Y cells insulted by a mix of glucosamine and glucose. Here, PEA directly counteracted inflammation and mitochondrial dysfunction in a PPAR-α-dependent manner since the pharmacological blockade of the receptor reverted its effects. Our results strengthen the therapeutic potential of PEA in obesity-related neuropsychiatric comorbidities, controlling neuroinflammation, BBB disruption, and neurotransmitter imbalance involved in behavioral dysfunctions.

Cell Metabolism

评语： 

本文通过控制WD喂养的时间，构建了代谢没有明显异常但认知层面已经出现问题的小鼠模型，并解析了孕烯醇酮在其中的神经机制，同时也在长期WD喂养出现代谢异常的小鼠中进行了验证。对代谢状态的精确调控分离出代谢状态的变量，提示高脂高糖饮食在造成肥胖之前就已经通过影响神经活动来损伤认知功能。表明除了通过达到肥胖结局后影响免疫和胰岛素敏感性从而影响智力的机制之外，还存在其他的机制。另一方面这篇文章发现POMC神经元除了调控摄食、能量稳态之外的功能，拓展了我们对经典“抑食神经元”的认识。

关键词： 

Pregnenolone; Arc; POMC; recognition

文章链接 ： 

https://doi.org/10.1016/j.cmet.2021.12.023

Abstract

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone’s effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.