OBJECTIVEFibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.RESEARCH DESIGN AND METHODSTo test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21.RESULTSWhen obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice.CONCLUSIONSThese data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.

Background & Aims Fibroblast growth factor 21 (FGF21) is a hepatic protein that plays a critical role in metabolism, stimulating fatty acid oxidation in liver and glucose uptake in fat. Systemic administration to obese rodents and diabetic monkeys leads to improved glucose homeostasis and weight loss. In rodents, FGF21 increases with fasting and consumption of a ketogenic diet (KD). In humans, FGF21 correlates with body mass index, but studies evaluating other parameters show inconsistent results. We examined FGF21 serum levels in lean and obese individuals and in response to dietary manipulation. We also evaluated FGF21 serum levels and liver mRNA expression in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods Serum FGF21 was measured after an overnight fast in individuals with BMI ranging from normal to obese. Volunteers fasted for 16 or 72 hours and then ate a standard meal. Another group consumed KD for 12 days. Serum FGF21 and hepatic mRNA expression were measured in obese individuals with NAFLD or NASH. Results There was a positive correlation between BMI and FGF21. There was no change in FGF21 in response to a short fast or KD. A non-statistically significant fall in FGF21 levels was seen after a 72 hour fast. Hepatic FGF21 mRNA expression was significantly elevated in NAFLD, which correlated with a substantial increase in serum FGF21. In NASH, serum FGF21 but not liver mRNA was increased. Conclusion FGF21 correlates with BMI and may be a novel biomarker for NAFLD but is not nutritionally regulated in humans.

Adipose tissue plays a central role in the control of energy homeostasis through the storage and turnover of triglycerides and through the secretion of factors that affect satiety and fuel utilization. Agents that enhance insulin sensitivity, such as rosiglitazone, appear to exert their therapeutic effect through adipose tissue, but the precise mechanisms of their actions are unclear. Rosiglitazone changes the morphological features and protein profiles of mitochondria in 3T3-L1 adipocytes. To examine the relevance of these effects in vivo, we studied white adipocytes from ob/ob mice during the development of obesity and after treatment with rosiglitazone. The levels of approximately 50% of gene transcripts encoding mitochondrial proteins were decreased with the onset of obesity. About half of those genes were upregulated after treatment with rosiglitazone, and this was accompanied by an increase in mitochondrial mass and changes in mitochondrial structure. Functionally, adipocytes from rosiglitazone-treated mice displayed markedly enhanced oxygen consumption and significantly increased palmitate oxidation. These data reveal mitochondrial remodeling and increased energy expenditure in white fat in response to rosiglitazone treatment in vivo and suggest that enhanced lipid utilization in this tissue may affect whole-body energy homeostasis and insulin sensitivity. IntroductionThe ability of brown adipose tissue to affect whole-body metabolism upon thermogenic stress has been known for many years (1, 2). More recently, the important contribution of white adipose tissue (WAT) to the control of energy homeostasis has been recognized with the study of tissue-specific knockout models and the discovery of adipocyte-specific secreted factors that have powerful effects on fuel metabolism (3, 4). These observations have raised many as-yetunanswered questions about the mechanisms by which adipocytes maintain their energy homeostasis as well as sense and respond to the metabolic requirements of the organism.Brown adipocytes contain a large complement of mitochondria that serve as a source of heat generated as a consequence of flow through the electron transport chain under uncoupled conditions elicited by uncoupling protein 1 (UCP-1). Recently we reported that adipogenesis of the 3T3-L1 cell line, representative of white adipocytes, is also accompanied by a stimulation of mitochondrial biogenesis (5). The need for a large mitochondrial mass in white fat can be linked to key functions of the adipocyte that require mitochondrial function. For example, adipocytes must generate glycerol 3-phosphate at a rate sufficient to sustain triglyceride synthesis, and for this the glyceroneogenic pathway and

Peroxisome proliferator-activated receptor ␥ (PPAR␥) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPAR␥ target genes are induced during adipogenesis, but others, such as glycerol kinase (GyK), are expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored the mechanism whereby an exogenous PPAR␥ ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPAR␥-response element to which endogenous PPAR␥ is recruited in adipocytes. However, unlike the classic PPAR␥-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by nuclear receptor corepressors in adipocytes. TZDs trigger the dismissal of corepressor histone deacetylase (HDAC) complexes and the recruitment of coactivators to the GyK gene. TZDs also induce PPAR␥-Coactivator 1␣ (PGC-1␣), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPAR␥ target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms.