Brown adipocytes are derived from undifferentiated mesenchymal stem cells. In contrast to white adipocytes, differentiation of brown adipocytes is under the influence of a different pair of transcription factors. When the zinc-finger protein known as PR domain containing 16 (PRDM16) is activated, mesenchymal stem cells synthesize several members of the PPAR coactivator-1 (PGC-1) family of transcription factors. Therefore, PRDM16/PGC-1 is regarded as a “master switch” regulator in the brown adipocytes’ differentiation. These factors in turn regulate expression of genes (i.e., UPC-1) that control brown fat differentiation. The UPC-1 gene encodes a specific mitochondrial protein called uncoupling protein (UCP-1) or thermogenin (a 33-kilodalton inner mitochondrial membrane protein) is essential for brown adipocytes metabolism (thermogenesis). Clinical observations confirm that under normal conditions brown adipose tissue can expand in response to increased blood levels of norepinephrine. This becomes evident in patients with pheochromocytoma, an endocrine tumor of adrenal medulla secreting excessive amounts of epinephrine and norepinephrine. In these individuals, the  FOLDER 9.1
Clinical Correlation: Obesity
Obesity is epidemic in the United States. According to current estimates by the National Institutes of Health (NIH), about two-thirds of Americans are considered to be obese, and 300,000 die annually from obesity-related metabolic diseases (i.e., diabetes, hypertension, cardiovascular dis-eases, and cancer). An individual is considered obese when the percentage of body fat exceeds the average per-centage for the individual’s age and sex. The prevalence of obesity has increased in the last decade from 12% to 18%. The increases are seen in both sexes and at all so-cioeconomic levels, with the greatest increase reported in the 18to 29-year-old age group. The body mass index (BMI), expressed as weight/ height2, is closely correlated with the total amount of body fat and is commonly used to classify overweight and obe-sity among adults. A BMI of approximately 25 kg/m2 is considered normal. A BMI greater than 27 kg/m2, which correlates to an excess body weight of approximately 20%, is considered a health risk. Obesity is associated with an increased risk of mortality as well as with many diseases such as hypertension, car-diovascular diseases, diabetes, and cancer. It is a chronic condition that develops as a result of an interaction be-tween a person’s genetic makeup and his or her environ-ment. Obesity genes encode the molecular components of the short-term and long-term weight regulation systems, which include leptin, ghrelin, and other factors that regulate energy balance. In addition, several of these factors modu-late glucose metabolism by adipose tissue and contribute to the development of insulin resistance, which is associ-ated with type 2 diabetes. Intensive research directed to-ward adipocyte-derived proteins may in the future provide potential drugs for reducing obesity and overcoming insulin resistance. blood vesselblood vessel connectiveconnective tissue septatissue septa
FIGURE 9.5 • Brown adipose tissue. a. Photomicrograph of brown adipose tissue from a newborn in an H&E–stained paraffin preparation. The cells contain fat droplets of varying size. 150. b. This photomicrograph, obtained at a higher magnification, shows the brown adipose cells with round and often centrally located nuclei. Most of the cells are polygonal and closely packed, with numerous lipid droplets. In some cells, large lipid droplets displace nuclei toward the cell periphery. A network of collagen fibers and capillaries surrounds the brown adipose cells. 320.