Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21

OBJECTIVE

Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels.

RESEARCH DESIGN AND METHODS

The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.

RESULTS

Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.

CONCLUSIONS

The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.Fibroblast growth factor (FGF)-21 is a recently discovered metabolic regulator of fasting metabolism. FGF-21 activates glucose uptake in adipocytes, protects animals from diet-induced obesity when overexpressed in transgenic mice, and lowers blood glucose and triglyceride levels when administered to diabetic rodents (1–3). Comparably, glucose- and triglyceride-lowering effects were found in diabetic rhesus monkeys during chronic FGF-21 treatment over a period of 6 weeks (4). Therefore, FGF-21 was assumed to be a novel target with potential antidiabetic properties, which might be useful in the treatment of hyperglycemia, insulin resistance, and hyperlipidemia.However, human data did not directly support these assumptions, since increased serum FGF-21 levels were found in obese individuals, patients with type 2 diabetes, and subjects with metabolic syndrome (5,6). In addition FGF-21 levels correlated positively not only with adiposity but also with fasting insulin and triacylglycerols (5). A recent study (3) reported a significant increase of FGF-21 levels during prolonged fasting. This process appeared to be peroxisome proliferator–activator receptor (PPAR) α–dependent (2,3), although exact mechanisms leading to fasting-induced FGF-21 elevations are yet unknown.Various data support that metabolic parameters themselves can modulate the circulating levels of hormones and adipokines (7–10). Thus, free fatty acids (FFAs) activate PPARs and were found to be elevated in fasting conditions. We therefore speculated that FFAs themselves might regulate FGF-21. This hypothesis is supported by recent data demonstrating that FGF-21 levels are positively associated with FFAs (11) and triacylglycerols (3) in a cross-sectional study population of nondiabetic individuals. Although the direction of that relation is unclear in a cross-sectional study, it offers a potential mechanism linking starvation to the increased levels of FGF-21. We therefore investigated the effect of fatty acids on FGF-21 secretion in HepG2 cells in vitro. Based on these in vitro data, we performed a randomized controlled trial to explore whether an increase in circulating FFAs and triacylglycerols modifies FGF-21 levels in humans. Since an increase of FFAs is known to induce insulin resistance and hyperinsulinemia, the effect of insulin on FGF-21 was additionally investigated by performing a hyperinsulinemic-euglycemic clamp at baseline of a noncontrolled, rosiglitazone intervention trial. As some recent animal data (12) also suggested a PPARγ-dependent regulation of FGF-21, we finally evaluated the effect of the PPARγ agonist, rosiglitazone, in that human trial.     

Effect of low-level laser therapy after implantation of poly-<Emphasis Type="SmallCaps">L</Emphasis>-lactic/polyglycolic acid in the femurs of rats

This study evaluated the use of red and infrared lasers on tissue surrounding the femurs of 60 rats randomly divided into three groups after implantation of bioabsorbable plates. The control group were not subjected to laser irradiation; group A was treated with red laser [indium–gallium–aluminum–phosphide (InGaAlP) laser, wavelength 685 nm, 35 mW, continuous wave (CW), Ø?=?0.06 cm, 2.23 min], and group B was subjected to infrared laser [gallium–aluminum–arsenium (GaAlAs) laser, wavelength 830 nm, 50 mw, CW, Ø?=?0.06 cm, 1.41 min], both at 10 J/cm². Samples were stained with hematoxylin and eosin (H&;E) and examined microscopically. Results showed that the laser irradiation had had a positive photobiomodulation effect on inflammation, confirmed by a better histologic pattern than that of the control group at 3 days and 7 days. Semiquantitative analysis revealed that groups A and B had a histologic score significantly greater than that of the control group at 3 days. At 21 days, histomorphometric analysis revealed a more intense inflammation in the red laser group than in the other groups. We concluded that low-level laser therapy (LLLT) has positive effects on the photobiomodulation of inflammation in the tissues surrounding the poly-L-lactic/polyglycolic acid (PLLA/PGA) bioabsorbable plate. It stimulated vascularization, fibroblast proliferation, and collagen deposition.     

Processing of facial affect under social threat in socially anxious adults: mood matters

Background: An important function of the human face is to communicate approval or disapproval toward others. Because socially anxious individuals are overly concerned about disapproval by others, it has been hypothesized that those individuals are faster at processing negative, specifically angry facial expressions than nonanxious individuals, especially under conditions of social threat. Method: To test this hypothesis, 25 socially anxious individuals and 24 nonanxious controls were asked to classify facial expressions associated with anger, sadness, fear, disgust, happiness, and surprise. Half of the participants performed this task while being confronted with social threat. Results: High socially anxious participants were faster than controls at classifying angry, sad, and fearful faces when confronted with social threat. No group difference was observed under the no‐threat condition. Conclusions: The findings suggest that socially anxious individuals are more hypervigilant toward threat‐related social cues, and that the processing of facial affect is dependent on the person's emotional state. Depression and Anxiety, 2009. © 2008 Wiley‐Liss, Inc.     

A low cost instrumented glove for extended monitoring and functional hand assessment

A wearable finger flexion monitor developed to measure hand function in individuals with hand dysfunction was evaluated for feasibility, measurement repeatability and reliability, fidelity of wireless transmission, and user acceptance. Configuration of the monitor allows use in situations when a traditional measurement glove cannot be worn. Five healthy individuals participated in the study of repeatability, while 10 healthy individuals and 10 individuals with acquired brain injury participated in trials to assess feasibility and user comfort. Repeatability results showed an overall error of 3.4°, compared to 5.5° and 5.7° reported with other sensor gloves, and to manual measurements (5–8°). Intraclass coefficient of reliability (using coefficient alpha) averaged 0.95. User feedback regarding comfort of the monitor was very high. Loss of data during wireless transmission was no greater than 1.2%. Results demonstrate that the monitor has a strong potential to be used as a tool for objective hand function evaluation in the home and community for both short- and long-term monitoring.     

Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial

PURPOSE: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy. METHODS: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, double-blind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex. RESULTS: "Active" rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability). CONCLUSIONS: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to "active" rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.     

Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential

Transcranial magnetic stimulation (TMS) is a 20-year-old technique originally introduced to noninvasively investigate nervous propagation along the corticospinal tract, spinal roots, and peripheral nerves in humans. TMS is extensively used in clinical neurophysiology, including rehabilitation and intraoperative monitoring. Single-pulse TMS and other more recent versions (paired-pulse TMS, repetitive TMS, integration with structural and functional MRI, and neuronavigation) allow motor output to be mapped precisely to a given body district. Moreover, TMS can be used to evaluate excitatory/inhibitory intracortical circuits and to provide information on brain physiology and pathophysiology of various neuropsychiatric diseases as well as on the mechanisms of brain plasticity and of neuroactive drugs. TMS applied over nonmotor areas made it possible to extend research applications (often complementary with other functional neuroimaging techniques) in several fields of psychophysiology, causally testing brain-behavior relationships. Being able to induce relatively long-lasting excitability changes, repetitive TMS has made the treatment of neuropsychiatric diseases linked with brain excitability dysfunctions possible. These uses, however, warrant further large-scale studies. In emerging fields of research, TMS-EEG co-registration is considered a promising approach to evaluate corticocortical connectivity and brain reactivity with high temporal resolution. However, safety and ethical limitations of TMS technique need a high level of vigilance.     

Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat

The present study investigated the influence of chronic cocaine treatment on genital reflexes associated with paradoxical sleep deprivation (PSD), and possible alterations in hippocampus neurogenesis of the male rat. At 21 days of age, the rats were distributed into two groups and injected with saline or cocaine (7 mg/kg, three times a week for 12 weeks). At age 90 days, they were submitted to a four-day period of PSD (PSD groups) or maintained in home-cages (control groups), challenged with saline or cocaine administration, and placed in observation cages to assess genital reflexes. Two additional groups were used to quantify neurogenesis. PSD rats treated chronically with cocaine and challenged with saline did not differ from their respective control groups. The association of PSD with cocaine potentiated penile erection (PE) when compared to PSD-saline (saline challenged) rats, and these effects were similar to those observed in long-term cocaine treated rats. The bromodeoxyuridine (BrdU) assay indicated a reduction in BrdU-positive cells in the adult hippocampus after chronic cocaine treatment. These findings show that long-term cocaine treatment from brain development through adulthood had a marked effect on sexual responses and neuronal proliferation.