Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease

Abstract

Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn’s disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn’s disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn’s disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn’s disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.

Immune modulatory effect of a novel 4,5-dihydroxy-3,3´,4´-trimethoxybibenzyl from Dendrobium lindleyi

“…in which CD14 dim was demonstrated to respond poorly to agonists of TLR1, TLR2 and TLR4 [ 34 ]. The inflammatory cytokine TNF has been shown to be involved in many biological processes including fever, apoptosis, and infection-induced cachexia [ 16 ], as well as in inflammation-associated diseases, for example rheumatoid arthritis [ 35 ], acquired generalized lipodystrophy and combined Crohn’s disease [ 36 ], Crohn's disease [ 37 ], and type 2 diabetes [ 38 ]. Moreover, chemokine such as TNF can also induce activate inflammatory responses, and are implicated in the regulation of tumor development and growth via regulation of tumor-associated angiogenesis, by activation of host immunological responses or by direct inhibition of tumor cell proliferation [ 39 ].…”

Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders?

“…Leptin is not only increased after high fat intake [96] and associated with obesity [97], but also connected with obesity-linked mucosal intestinal inflammation [98]. Leptin treatment directly induces epithelial inflammation [99] and has been shown to increase proinflammatory activity of natural killer (NK) and CD8+ T-cells as well as TNFα-expressing cells in the gut, leading to autoimmune gut disease aggravation [100]. Proinflammatory macrophages are also shown to depend highly on glycolysis for their energy homeostasis [101].…”

There and Back Again: Leptin Actions in White Adipose Tissue

“…In Crohn’s disease where fat-wrapping is one of the main characteristics, leptin has been implicated in the intestinal inflammation associated with these patients; in this way, hyperplastic mesenteric fat, wrapping inflamed intestinal segments, produce leptin and other adipokines that modulate the systemic immune cell composition and the intestinal cell function [ 247 , 248 ]. These patients can suffer at the same time acquired lipodystrophy; in this context, where leptin treatment could have benefits, it is important considerer that also could result in an aggravation of the intestinal inflammation [ 249 ]. In the same context, in inflammatory bowel disease (IBD) the mesenteric WAT is hypertrophied; these patients are characterized by suffering anorexia and altered body composition.…”