Loss of pericyte smoothened activity in mice with genetic deficiency of leptin

Abstract

BackgroundObesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation.ResultsWe found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage.ConclusionsLeptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-017-0135-y) contains supplementary material, which is available to authorized users.

Leptin Receptor Expression in Mouse Intracranial Perivascular Cells

“…Recent studies have associated leptin and LepRb deficiency with pericytopathy in peripheral organs including the liver, pancreas, and bone marrow ( Choi et al, 2010 ; Chien et al, 2016 ; Yue et al, 2016 ; Haley and Lawrence, 2017 ; Xie et al, 2017 ). Using qPCR studies, we further characterized the expression of different leptin receptor isoforms and perivascular markers in the hypothalamus and meninges of LepRb-deficient mice.…”

“…It is therefore tempting to speculate that leptin signaling may also play a role in brain diseases with an inflammatory component, perhaps via the regulation of the perivascular coverage and leukocyte infiltration. Lastly, several studies reported peripheral pericyte loss in mice deficient for leptin or LepRb ( Chien et al, 2016 ; Haley and Lawrence, 2017 ; Xie et al, 2017 ), and further demonstrated that LepRb signaling played an important role in the proliferation and differentiation of peripheral pericytes ( Saxena et al, 2002 ; Choi et al, 2010 ; Zhou et al, 2014 ; Yue et al, 2016 ). This suggests that intact LepRb signaling is required for normal perivascular cells activities.…”

Metformin Mitigates Fibrosis and Glucose Intolerance Induced by Doxorubicin in Subcutaneous Adipose Tissue

“…This increase in fibrosis leads to complications in adipose tissue such as high extracellular matrix rigidity and reduced expandability. It also induces ectopic lipid deposition, which leads to insulin resistance and impairment of metabolic pathways ( Xie et al, 2017 ).…”

Dyslipidemia Is a Major Factor in Stem Cell Damage Induced by Uncontrolled Long-Term Type 2 Diabetes and Obesity in the Rat, as Suggested by the Effects on Stem Cell Culture

“…Our previous study (11) defined the in situ impairment by a systemic or local noxious milieu in the tissue of origin, particularly long-term uncontrolled-type 2 diabetes (UC-T2D) and obesity in a rat model, and showed that in addition to their phenotype imprinting, these stem cells had lost the capacity to exert tissue and functional repair when implanted into another tissue damaged by the same environment in either syngenic or autologous hosts. There are some reports describing deleterious effects of the T2D milieu and its associated oxidative stress on the microenvironment impairing stem cells, inducing apoptosis, interfering with wound healing capacity, and other effects (e.g., 12–15), as well as obesity per se or associated with diabetes on the number of stem cells and progenitor cells, their lifespan, and other effects (e.g., 16–18). The impairment of stem cells was ascribed in some cases to dyslipidemia (e.g., 19, 20).…”