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.
Highlights
Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage
white adipose tissue (WAT) in ob/ob mice is very abnormal, becoming progressively populated by hypertrophic insulin-insensitive adipocytes with age, as is typical of WAT in obese humans [9]. In these leptin-target tissues, we focused on resident perivascular cells that wrap around the tissue microvasculature, because they are vital for tissue health and regulate a variety of responses that are often defective in obesity, such as blood flow within tissues, vascular permeability, and local wound healing responses, including inflammation, angiogenesis, matrix remodeling and tissue regeneration [10]
Leptin is required for hedgehog pathway activation in liver resident pericytes Liver-resident pericytes in healthy adult livers express both leptin and its receptors, and leptin signaling activity increases as quiescent (Q)- Hepatic stellate cell (HSC) trans-differentiate to become myofibroblastic (MF)-HSCs [15, 24]
Summary
Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Leptin-deficient ob/ob mice have been studied intensively as a model of obesity and its comorbidities: ob/ob mice are hyperphagic and morbidly obese, and dysmorphic and prone to various types of tissue damage [4, 5]. It remains unclear how deficiency of this single anorexogenic hormone profoundly disrupts functions in multiple tissues to generate this complex phenotype. One general concept is that leptin is a key component of the sensor that matches cellular energy utilization to available energy supplies
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