Ritwik Datta

Significance: The increasing prevalence of insulin resistance in the current obesity epidemic creates a significant need for ongoing investigations into the mechanisms that modulate insulin resistance. Long-term treatment of diabetic patients with high doses of insulin, especially in those that are obese, may cause further weight gain and exacerbate the risk of developing cancers. The work presented here demonstrates a previously unappreciated regulatory pathway by which insulin initiates dampening and/or termination of its own signaling pathway through an integrin-dependent pathway. These data identify a pathway that can potentially be targeted to reduce insulin requirements in patients with diabetes.

Although aging represents the most important epidemiologic risk factor for fibrotic disease, the reasons for this are incompletely understood. Excess collagen deposition in tissues is the sine qua non of tissue fibrosis and can be viewed as an imbalance between collagen production and collagen degradation. Yet we still lack a detailed understanding of the changes that take place during development, maturation, and aging in extracellular matrix (ECM) dynamics. Resolution of fibrosis is impaired in aging, and this impairment may explain why age is the most important risk factor for fibrotic diseases, such as idiopathic pulmonary fibrosis. However, ECM dynamics and impaired resolution of fibrosis in aging remain understudied. Here we show that cell-mediated collagen uptake and degradation are diminished in aged animals and this finding correlates with downregulation of the collagen endocytic receptor mannose receptor, C-type 2 ( Mrc2 ). We identify myeloid zinc finger-1 as a potentially novel transcriptional regulator of Mrc2 , and both this transcription factor and Mrc2 are downregulated in multiple tissues and organisms in an age-dependent manner. Thus, cell-mediated degradation of collagen is an essential process that promotes resolution of fibrosis, and impairment in this process contributes to age-related fibrosis.

At the simplest level, obesity is the manifestation of an imbalance between caloric intake and expenditure; however, the pathophysiological mechanisms that govern the development of obesity and associated complications are enormously complex. Fibrosis within the adipose tissue compartment is one such factor that may influence the development of obesity and/or obesity-related comorbidities. Furthermore, the functional consequences of adipose tissue fibrosis are a matter of considerable debate, with evidence that fibrosis serves both adaptive and maladaptive roles. Tissue fibrosis itself is incompletely understood, and multiple cellular and molecular pathways are involved in the development, maintenance, and resolution of the fibrotic state. Within the context of obesity, fibrosis influences molecular and cellular events that relate to adipocytes, inflammatory cells, inflammatory mediators, and supporting adipose stromal tissue. In this Review, we explore what is known about the interplay between the development of adipose tissue fibrosis and obesity, with a view toward future investigative and therapeutic avenues.