Abstract
Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis. Male and female cU2 mice exhibit significant weight gain, accompanied by marked increase in abdominal fat mass and metabolic abnormalities, including reduction of both glucose clearance rate and insulin sensitivity, as early as two months of age. Adipogenesis derailment at this early age is suggested by decreased expression of adiponectin, the fat mass and obesity-associated gene, and the adiponectin receptor R1, coupled with a reduction of the brown fat biomarker PAT2 and the adipogenesis inhibitor SIRT1. Notably, adiponectin is an important adipokine and an essential regulator of glucose and fatty acid homeostasis. cU2 mice may provide a crucial animal model for investigating the role of miR-34c in early onset insulin resistance and visceral fat mass increase, contributing to accelerated body weight gain and metabolic disorders. Intervention in this dysregulation may open a new preventive strategy to control early-life weight gain and abnormal insulin resistance, and thus prevalent adult and late life obesity.
Highlights
Available animal models for obesity are numerous, exemplified by the nutritional approach via high fat diet regimen, and genetic alteration of leptin signaling leading to overeating[1]
We report here the generation of a transgenic mouse line, cU2, with the human miR-34c transgene driven by a ubiquitin promoter for early and generalized expression[26] of miR-34c in all tissues
Our data suggest that ubiquitous overexpression of miR-34c may cause these early life physiological changes, which are recognized risk factors for adult obesity and diabetes, and that miR-34c transgenic mice may be a good animal model for unraveling the “Pandora’s box” of developmental origins of adult obesity
Summary
Available animal models for obesity are numerous, exemplified by the nutritional approach via high fat diet regimen, and genetic alteration of leptin signaling leading to overeating[1] Use of these models has unveiled a wealth of knowledge concerning adipogenic pathways and appetite control hormones via hypothalamus[2]. These animal model studies clearly demonstrate that eating habits, in addition to other life style habits such as lack of exercise, are among many factors contributing to adult obesity This approach does not address the emerging suggestion of a “developmental origin of obesity”[3,4,5] occurring in early life, from prenatal to childhood and adolescent stages. Excessive activation of miR-34 cluster expression, while endowing the gain of tumor suppression in early life, may be at the cost of altering normal adipogenic pathways and leading to early life obesity
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