Mi-Seon Shin

Leptin-promoted cilia assembly is critical for normal energy balance

The majority of mammalian cells have nonmotile primary cilia on their surface that act as antenna-like sensory organelles. Genetic defects that result in ciliary dysfunction are associated with obesity in humans and rodents, which suggests that functional cilia are important for controlling energy balance. Here we demonstrated that neuronal cilia lengths were selectively reduced in hypothalami of obese mice with leptin deficiency and leptin resistance. Treatment of N1 hypothalamic neuron cells with leptin stimulated cilia assembly via inhibition of the tumor suppressors PTEN and glycogen synthase kinase 3β (GSK3β). Induction of short cilia in the hypothalamus of adult mice increased food intake and decreased energy expenditure, leading to a positive energy balance. Moreover, mice with short hypothalamic cilia exhibited attenuated anorectic responses to leptin, insulin, and glucose, which indicates that leptin-induced cilia assembly is essential for sensing these satiety signals by hypothalamic neurons. These data suggest that leptin governs the sensitivity of hypothalamic neurons to metabolic signals by controlling the length of the cells antenna.

Clusterin/ApoJ enhances central leptin signaling through Lrp2‐mediated endocytosis

Hypothalamic leptin signaling plays a central role in maintaining body weight homeostasis. Here, we show that clusterin/ApoJ, recently identified as an anorexigenic neuropeptide, is an important regulator in the hypothalamic leptin signaling pathway. Coadministration of clusterin potentiates the anorexigenic effect of leptin and boosts leptin‐induced hypothalamic Stat3 activation. In cultured neurons, clusterin enhances receptor binding and subsequent endocytosis of leptin. These effects are mainly mediated through the LDL receptor‐related protein‐2 (Lrp2). Notably, inhibition of hypothalamic clusterin, Lrp2 or endocytosis abrogates anorexia and hypothalamic Stat3 activation caused by leptin. These findings propose a novel regulatory mechanism in central leptin signaling pathways.

Long-term changes in serum IGF-1 levels after successful surgical treatment of growth hormone-secreting pituitary adenoma.

BACKGROUND Successful treatment of acromegaly is known to normalize serum insulin-like growth factor 1 (IGF-1) levels within days after surgery. However, our clinical observations indicate that many cases of acromegaly show delayed normalization of serum IGF-1 levels after complete tumor resection. OBJECTIVE To study long-term changes of the serum IGF-1 levels in acromegalic patients for whom surgical treatment was thought to be successful. METHODS A retrospective observational study was performed with 46 acromegalic patients with no residual tumor on sellar magnetic resonance imaging, and a nadir growth hormone of less than 0.4 μg/L on a postoperative oral glucose tolerance test. RESULTS In all patients, serum IGF-1 levels returned to the normal reference values for age and sex during the observational period (12-132 months). The mean duration from the time of surgery until IGF-1 normalization was 10 months (range, 3 days-57 months). Twenty-seven patients (59%) reached normal IGF-1 ranges within 3 months of surgery, whereas 19 patients (41%) experienced delayed (>3 months) IGF-1 normalization. Eleven patients (24%) recovered normal IGF-1 levels 12 to 57 months after surgery. The possibility of delayed IGF-1 cure was increased 8.8-fold with an immediate postoperative IGF-1 level increase of 100 μg/L. CONCLUSION Satisfactory remission of acromegaly by IGF-1 criteria was delayed in a large proportion of acromegalic patients, especially those with high postoperative IGF-1 levels. Hence, additional treatment can be delayed in clinically stable acromegalic patients who show no evidence of residual tumors on postoperative magnetic resonance imaging and a normal growth hormone suppressive response to a glucose load.

The Prevalence of Peripheral Arterial Disease in Korean Patients with Type 2 Diabetes Mellitus Attending a University Hospital

Background Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis and is associated with significant morbidity and mortality. Diabetes is known to increase the risk of PAD two- to four-fold. The prevalence of PAD in Korean diabetic patients has not been established. In this study, we investigated the prevalence of PAD in Korean patients with type 2 diabetes attending a large university hospital and analyzed the factors associated with PAD. Methods A total of 2,002 patients with type 2 diabetes who underwent ankle-brachial index (ABI) measurement in an outpatient clinic were enrolled. PAD was defined as an ABI ≤0.9. Clinical characteristics of 64 patients with PAD were compared with those of 192 age- and sex-matched control patients without PAD. Results Of the 2,002 type 2 diabetic patients, 64 (3.2%) were diagnosed as having PAD. PAD was associated with higher prevalences of retinopathy, nephropathy, neuropathy, cerebrovascular and coronary artery disease. Patients with PAD had higher systolic blood pressure and serum triglyceride level and reported higher pack-years of smoking. Multivariate analysis showed that the presence of micro- and macrovascular complications and high systolic blood pressure are factors independently associated with PAD. Conclusion The prevalence of PAD in diabetic patients was 3.2%, suggesting that the prevalence in Korean diabetic patients is lower than that of patients in Western countries.

Involvement of Progranulin in Hypothalamic Glucose Sensing and Feeding Regulation

Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions, including modulation of wound healing and inflammation. Hypothalamic PGRN has been implicated in the development of sexual dimorphism. In the present study, a potential role for PGRN in the hypothalamic regulation of appetite and body weight was investigated. In adult rodents, PGRN was highly expressed in periventricular tanycytes and in hypothalamic neurons, which are known to contain glucose-sensing machinery. Hypothalamic PGRN expression levels were decreased under low-energy conditions (starvation and 2-deoxy-D-glucose administration) but increased under high-energy condition (postprandially). Intracerebrovetricular administration of PGRN significantly suppressed nocturnal feeding as well as hyperphagia induced by 2-deoxyglucose, neuropeptide Y, and Agouti-related peptide. Moreover, the inhibition of hypothalamic PGRN expression or action increased food intake and promoted weight gain, suggesting that endogenous PGRN functions as an appetite suppressor in the hypothalamus. Investigation of the mechanism of action revealed that PGRN diminished orexigenic neuropeptide Y and Agouti-related peptide production but stimulated anorexigenic proopiomelanocortin production, at least in part through the regulation of hypothalamic AMP-activated protein kinase. Notably, PGRN was also expressed in hypothalamic microglia. In diet-induced obese mice, microglial PGRN expression was increased, and the anorectic response to PGRN was blunted. These findings highlight a physiological role for PGRN in hypothalamic glucose-sensing and appetite regulation. Alterations in hypothalamic PGRN production or action may be linked to appetite dysregulation in obesity.

The duration of sulfonylurea treatment is associated with β-cell dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND This study investigated the incidence of β-cell dysfunction and the clinical and biochemical factors affecting that in patients with type 2 diabetes having more than 3 years of follow-up. SUBJECTS AND METHODS β-Cell dysfunction was assessed by measuring changes in the fasting serum C-peptide concentrations. Patients were classified into two groups: cases showing a decreased (Group D) or an unchanged or increased (Group I) C-peptide concentration from the baseline. RESULTS Of the 504 patients included in this study, 259 (51%) showed decreased C-peptide concentrations, of whom 20% showed a decrease of ≥50%. Most patients, however, had a final C-peptide concentration of ≥1 ng/mL, with only 18 (4%) individuals having a level <0.6 ng/mL. Patients in Group D had a longer duration of diabetes, higher initial hemoglobin A1c concentration, and longer treatment durations with sulfonylurea and insulin compared with Group I. After adjusting for diabetes duration and C-peptide follow-up period, the duration of sulfonylurea treatment was found to be the only factor independently associated with decreases in the C-peptide concentration. CONCLUSIONS Although β-cell function deteriorates over time in patients with type 2 diabetes, these cases mainly have fasting serum C-peptide concentrations of ≥1 ng/mL. A longer treatment duration with sulfonylurea is associated with a more rapid decline in the C-peptide concentration.

Various Oscillation Patterns of Serum Fibroblast Growth Factor 21 Concentrations in Healthy Volunteers

Background Fibroblast growth factor 21 (FGF21) was originally identified as a paroxysm proliferator activated receptor-α target gene product and is a hormone involved in metabolic regulation. The purpose of this study was to investigate the diurnal variation of serum FGF21 concentration in obese and non-obese healthy volunteers. Methods Blood samples were collected from five non-obese (body mass index [BMI] ≤23 kg/m2) and five obese (BMI ≥25 kg/m2) healthy young men every 30 to 60 minutes over 24 hours. Serum FGF21 concentrations were determined by radioimmunoassay. Anthropometric parameters, glucose, free fatty acid, insulin, leptin, and cortisol concentrations were also measured. Results The serum FGF21 concentrations displayed various individual oscillation patterns. The oscillation frequency ranged between 6 and 12 times per day. The average duration of oscillation was 2.52 hours (range, 1.9 to 3.0 hours). The peaks and troughs of FGF21 oscillation showed no circadian rhythm. However, the oscillation frequency had a diurnal variation and was lower during the light-off period than during the light-on period (2.4 vs. 7.3 times, P<0.001). There was no difference in the total frequency or duration of oscillations between non-obese and obese subjects, but obese individuals had increased numbers of larger oscillations (amplitude ≥0.19 ng/mL). Conclusion Various oscillation patterns in serum FGF21 concentration were observed, and reduced oscillation frequencies were seen during sleep. The oscillation patterns of serum FGF21 concentration suggest that FGF21 may be secreted into systemic circulation in a pulsatile manner. Obesity appeared to affect the amplitude of oscillations of serum FGF21.

Elevated serum ceruloplasmin levels are associated with albuminuria in Korean men with type 2 diabetes mellitus.

The aim of this study was to examine the possible association between serum ceruloplasmin, a copper carrying protein, and albuminuria in 456 males with type 2 diabetes. Multivariate regression analysis demonstrated that elevated serum ceruloplasmin was a determinant of albuminuria independently of conventional risk factors.

Regulation of Energy Balance by the Hypothalamic Lipoprotein Lipase Regulator Angptl3

Hypothalamic lipid sensing is important for the maintenance of energy balance. Angiopoietin-like protein 3 (Angptl3) critically regulates the clearance of circulating lipids by inhibiting lipoprotein lipase (LPL). The current study demonstrated that Angptl3 is highly expressed in the neurons of the mediobasal hypothalamus, an important area in brain lipid sensing. Suppression of hypothalamic Angptl3 increased food intake but reduced energy expenditure and fat oxidation, thereby promoting weight gain. Consistently, intracerebroventricular (ICV) administration of Angptl3 caused the opposite metabolic changes, supporting an important role for hypothalamic Angptl3 in the control of energy balance. Notably, ICV Angptl3 significantly stimulated hypothalamic LPL activity. Moreover, coadministration of the LPL inhibitor apolipoprotein C3 antagonized the effects of Angptl3 on energy metabolism, indicating that LPL activation is critical for the central metabolic actions of Angptl3. Increased LPL activity is expected to promote lipid uptake by hypothalamic neurons, leading to enhanced brain lipid sensing. Indeed, ICV injection of Angptl3 increased long-chain fatty acid (LCFA) and LCFA-CoA levels in the hypothalamus. Furthermore, inhibitors of hypothalamic lipid-sensing pathways prevented Angptl3-induced anorexia and weight loss. These findings identify Angptl3 as a novel regulator of the hypothalamic lipid-sensing pathway.

Three-dimensional isotropic fast spin-echo MR lymphangiography of T1-weighted and intermediate-weighted pulse sequences in patients with lymphoedema.

AIM To evaluate the feasibility of magnetic resonance (MR) lymphangiography acquired using three-dimensional (3D) isotropic T1-weighted fast spin-echo (FSE) and 3D isotropic intermediate-weighted FSE sequences, as the new method of MR lymphangiography, and to compare the results of these two methods in patients with lymphoedema. MATERIALS AND METHODS Thirty-three extremities of 27 patients with primary or secondary lymphoedema and who had undergone radionuclide lymphoscintigraphy and MR lymphangiography with 3D isotropic T1-weighted FSE and 3D isotropic intermediate-weighted FSE were included in the study. The results of both imaging techniques were independently reviewed by two readers in consensus who rated the lymphatic drainage pattern, the quality of the depiction of lymphatic vessels and lymph nodes, and the level of lymph vessel enhancement. The assessment scores of each imaging sequence were compared using the Wilcoxon signed-rank test. The results were expressed as means with standard deviations. RESULTS More lymphatic vessels were visualised on T1-weighted FSE than on intermediate-weighted FSE (p<0.001). As more lymphatic vessels were detected on T1-weighted FSE, the per-extremity grade of the lymphatic drainage pattern was higher (p=0.046) and the visible levels of lymph-vessel enhancement were also significantly higher (p=0.004) on the T1-weighted FSE sequence, whereas the conspicuity of lymph nodes was superior on intermediate-weighted FSE (p=0.004). CONCLUSION MR lymphangiography using the 3D FSE pulse sequence is a feasible and noticeable new technique of MR lymphangiography. Between the two applicable protocols used, T1-weighted FSE provided better information regarding lymphatic vessels and their drainage, whereas intermediate-weighted FSE has the advantage of depicting lymph nodes in lymphoedematous extremities.