Adipose plays critical roles in the regulation of energy homeostasis and acts as an integrator of various physiological pathways. It has been increasingly recognized that adipose dysfunction causes serious public health problems that are often associated with type 2 diabetes and cardiovascular disease. The prevalence of obesity and associated metabolic complications has dramatically increased globally and has become a major cause for morbidity and premature mortality in recent years. Primary adipocyte disorders such as lipodystrophy have gained less attention than obesity, namely because of their lower prevalence. Research into acquired and genetic lipodystrophy is becoming increasingly significant as it may provide new clues to decipher the biology of primary adipocyte disorders. The hope is that by understanding the molecular mechanisms at play in these disorders it will be possible to also shed light on the mechanisms involved in obesity. Autosomal dominant partial lipodystrophy has been associated with a number of genes including LMNA and PLIN1. Mutations in the LMNA gene result in what is termed Dunnigan-type familial partial lipodystrophy syndrome type 2 (FPLD2). The major clinical feature of this disorder is fat loss in the limbs and trunk, with elevated fat storage in the neck and face. In contrast, mutations in the PLIN1 gene appear to cause a more uniform reduction of adipocytes in all depots. Due to the loss of adipose, patients exhibit metabolic dysfunction such as insulin resistance, glucose intolerance, lowered plasma high-density-lipoprotein cholesterol, and accumulation of plasma triglycerides. They often develop diabetes mellitus, hypertriglyceridemia, and early- onset atherosclerosis. Interestingly, most of these clinical symptoms are also found in individuals with morbid obesity. While the physiological consequences of LMNA and PLIN1 mutations have been described, very little about the molecular events underlying these diseases is known because of the absence of an accurate model system. Human adipose is easily obtained, however primary adipocytes are difficult to maintain in culture and are not amenable to expansion. As consequence, in vitro systems for understanding mature primary adipocyte function do not exist. In an attempt to better understand the pathophysiology of primary adipocyte dysfunctions, we propose to determine whether LMNA and PLIN1-mutant adipocytes exhibit developmental or functional differences. This will involve the derivation of induced pluripotent cells from fibroblats carrying mutations in LMNA and PLIN1 and the generation of adipocytes from LMNA and PLIN1-mutant and control iPS cells.
We aim to elucidate the molecular events that lead to the development of primary adipocye disorders and seek to identify novel disease mechanisms. By examining two related but distinct forms of autosomal dominant lipodystrophy, we hope to improve our knowledge of adipose biology and dysfunction and facilitate the development of therapeutic interventions for not only lipodystrophy but also other adipose disorders such as obesity.
Broadly, the goal of this proposal is to determine whether LMNA and PLIN1-mutant adipocytes exhibit developmental or functional differences. This will involve the derivation of induced pluripotent cells from fibroblasts carrying mutations in LMNA and PLIN1 and the generation of adipocytes from human iPS cells. Ultimately, this strategy will improve our knowledge of adipose biology and dysfunction in primary adipocyte disorders and facilitate the development of therapeutic interventions for not only autosomal dominant partial lipodystrophy but also other adipose disorders such as obesity.
|Hendriks, William T; Warren, Curtis R; Cowan, Chad A (2016) Genome Editing in Human Pluripotent Stem Cells: Approaches, Pitfalls, and Solutions. Cell Stem Cell 18:53-65|
|Pope, Benjamin D; Warren, Curtis R; Parker, Kevin Kit et al. (2016) Microenvironmental Control of Adipocyte Fate and Function. Trends Cell Biol 26:745-755|
|Friesen, Max; Hudak, Carolyn S; Warren, Curtis R et al. (2016) Adipocyte insulin receptor activity maintains adipose tissue mass and lifespan. Biochem Biophys Res Commun 476:487-492|
|Moisan, Annie; Lee, Youn-Kyoung; Zhang, Jitao David et al. (2015) White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol 17:57-67|
|Roberts, Lee D; Boström, Pontus; O'Sullivan, John F et al. (2014) ?-Aminoisobutyric acid induces browning of white fat and hepatic ?-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 19:96-108|
|Ding, Qiurong; Regan, Stephanie N; Xia, Yulei et al. (2013) Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell 12:393-4|
|Ding, Qiurong; Lee, Youn-Kyoung; Schaefer, Esperance A K et al. (2013) A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 12:238-51|
|Ahfeldt, Tim; Schinzel, Robert T; Lee, Youn-Kyoung et al. (2012) Programming human pluripotent stem cells into white and brown adipocytes. Nat Cell Biol 14:209-19|