ABSTRACT
BACKGROUND: Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissue function is a research priority. The NR4A subfamily of nuclear receptors (NRs) (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) has emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver and muscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and their target genes are largely unknown. OBJECTIVE: To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identify potential NR4A target genes. DESIGN: Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primary human preadipocytes. Case-control comparison of omental (OM) adipose tissue. SUBJECTS: A total of 13 extremely obese patients undergoing biliopancreatic diversion with duodenal switch for fat loss, 12 extremely obese patients undergoing laparoscopic sleeve gastrectomy and 37 lean individuals undergoing hernia repair or laparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4A members and in silico promoter analysis based on microarray data. RESULTS: There was a strong upregulation of the NR4As in extreme obesity and normalization after fat loss. The NR4As were expressed at the highest level in stromal-vascular fraction compared with adipocytes, but were downregulated in both fractions after fat loss. Their expression levels were also significantly higher in OM compared with s.c. adipocytes in obesity. The NR4As were downregulated during differentiation of primary human preadipocytes. Moreover, the NR4As were strongly induced within 30 min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stress response, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4As in obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.
Subject(s)
Adipocytes/metabolism , Adipose Tissue/metabolism , DNA-Binding Proteins/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism , Obesity, Morbid/metabolism , Receptors, Steroid/metabolism , Receptors, Thyroid Hormone/metabolism , Weight Loss , Adult , DNA-Binding Proteins/genetics , Down-Regulation , Female , Follow-Up Studies , Gene Expression Regulation , Humans , Male , Middle Aged , Norway , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Nuclear Receptor Subfamily 4, Group A, Member 2/genetics , Obesity, Morbid/surgery , Prospective Studies , Receptors, Steroid/genetics , Receptors, Thyroid Hormone/genetics , Signal Transduction , Transcription Factors , Up-Regulation , Weight Loss/geneticsABSTRACT
BACKGROUND: The use of metformin in the treatment of diabetes mellitus type II is increasing. The drug has several advantageous metabolic effects, and is considered safe if not used in the presence of contraindications, in particular renal failure. MATERIAL AND METHODS: We present a patient with metformin associated lactic acidosis, to remind of a potentially lethal adverse reaction. We also review the literature about incidence and risk, prognosis and treatment of the disease. RESULTS: Our patient was a 72 year old woman with diabetes mellitus type II treated with metformin, who presented with acute renal failure, severe metabolic acidosis and circulatory failure. Treatment with bicarbonate buffer and vasopressors did not improve her condition, only after hemodialysis was her situation stabilised. INTERPRETATION: Metformin associated lactic acidosis must be considered in obscure metabolic acidosis in diabetic patients. The single most important therapeutic approach appears to be immediate hemodialysis.
