Inhibition of hypothalamic leukemia inhibitory factor exacerbates diet-induced obesity phenotype

Abstract

BackgroundThe consumption of large amounts of dietary fats can trigger an inflammatory response in the hypothalamus and contribute to the dysfunctional control of caloric intake and energy expenditure commonly present in obesity. The objective of this study was to identify chemokine-related transcripts that could be involved in the early stages of diet-induced hypothalamic inflammation.MethodsWe used immunoblot, PCR array, real-time PCR, immunofluorescence staining, glucose and insulin tolerance tests, and determination of general metabolic parameters to evaluate markers of inflammation, body mass variation, and glucose tolerance in mice fed a high-fat diet.ResultsUsing a real-time PCR array, we identified leukemia inhibitory factor as a chemokine/cytokine undergoing a rapid increase in the hypothalamus of obesity-resistant and a rapid decrease in the hypothalamus of obesity-prone mice fed a high-fat diet for 1 day. We hypothesized that the increased hypothalamic expression of leukemia inhibitory factor could contribute to the protective phenotype of obesity-resistant mice. To test this hypothesis, we immunoneutralized hypothalamic leukemia inhibitory factor and evaluated inflammatory and metabolic parameters. The immunoneutralization of leukemia inhibitory factor in the hypothalamus of obesity-resistant mice resulted in increased body mass gain and increased adiposity. Body mass gain was mostly due to increased caloric intake and reduced spontaneous physical activity. This modification in the phenotype was accompanied by increased expression of inflammatory cytokines in the hypothalamus. In addition, the inhibition of hypothalamic leukemia inhibitory factor was accompanied by glucose intolerance and insulin resistance.ConclusionHypothalamic expression of leukemia inhibitory factor may protect mice from the development of diet-induced obesity; the inhibition of this protein in the hypothalamus transforms obesity-resistant into obesity-prone mice.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0956-9) contains supplementary material, which is available to authorized users.

Molecular relationships between SARS-CoV-2 Spike protein and LIFR, a pneumonia protective IL-6 family cytokine

“…A dissection of the role of LIF and IL-6 in COVID-19 could guide targeting of the distinct signaling pathways for these IL-6 family cytokines as a means to develop therapeutics against COVID-19. Given that LIFR is required for protection of lungs in pneumonia and its ligand LIF has been associated with acute respiratory distress syndrome (ARDS), comorbidities such as obesity 92,93 , diabetes 94 , hypertension 95,96 , stroke 97 and kidney failure 98 , it may provide insights into why these conditions are associated with severe COVID-19. As LIFR is also important in the proliferation of olfactory neural progenitors which influence neuronal regeneration of the olfactory epithelium after injury 99,100 , it could have a direct role in the loss of smell in COVID-19 patients.…”

Myokines in Appetite Control and Energy Balance

“…High fat diet (HFD)-induced obesity in rodents is associated with hypothalamic inflammation, a pathological state that is a key characteristic of the disease. In rodents, LIF is downregulated in both the nucleus tractus solitarus of the brainstem and hypothalamus in response to HFD [83,84]. Importantly, LIF can act upon LIF receptors on POMC neurons in an anorexigenic manner by stimulating the release of alpha MSH [85].…”

Melanoma Progression under Obesity: Focus on Adipokines

“…However, LIF is probably a negative regulator during the adipogenous differentiation of human bone marrow mesenchymal stem cells [ 220 ]. It was observed that hypothalamic inhibition of this factor in obesity-resistant mice switched them into the obesity-prone phenotype, which indicates that this adipokine is an obesity-protectant [ 221 ]. On the other hand, a high-fat diet decreased the LIF gene transcription in the brain stems of rats which may contribute to permissive overconsumption and the development of diet-induced obesity [ 93 ].…”