Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMH ^GLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMH ^GLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMH ^GLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARC ^NPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.

Trabecular bone score (TBS) is a novel texture index that evaluates the pixel gray-level variations in lumbar spine dual-energy X-ray absorptiometry images and is related to bone microarchitecture independent of bone mineral density (BMD). We investigated lumbar spine TBS as an indicator for skeletal deterioration in diabetes. Cross-sectional data were collected from subjects participating in an ongoing prospective, community-based, cohort study from 2009 to 2010. We included 1229 men and 1529 postmenopausal women older than 50 years in the Ansung cohort. Biochemical parameters, lumbar spine TBS, and BMD from dual-energy X-ray absorptiometry images were measured. Lumbar spine TBS was lower in men with diabetes than in nondiabetic men (1.287 ± 0.005 vs 1.316 ± 0.003, P < .001), whereas lumbar spine BMD was higher in men with diabetes (1.135 ± 0.010 vs 1.088 ± 0.006 g/cm(2)). Lumbar spine TBS was lower in women with diabetes than in nondiabetic women only in an unadjusted model (1.333 ± 0.004 vs 1.353 ± 0.003). However, women younger than 65 years (n = 707) with diabetes had a lower TBS than those without diabetes, even after adjusted for covariates (P < .001). Diabetes was not associated with BMD at femur sites in both genders. TBS was negatively correlated with glycated hemoglobin, fasting plasma glucose, fasting insulin, and homeostasis model assessment for insulin resistance but not with homeostasis model assessment for β-cell function in both genders. The inverse association between lumbar spine TBS and insulin resistance may make it an indicator for determining skeletal deterioration in diabetic patients who have high BMD.

Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis. We investigated the role of FXR in regulating bone metabolism. We identified the expression of FXR in calvaria and bone marrow cells, which gradually increased during osteoblastic differentiation in vitro. In male mice, deletion of FXR (FXR^−/−) in vivo resulted in a significant reduction in bone mineral density by 4.3% to 6.6% in mice 8 to 20 weeks of age compared with FXR^+/+ mice. Histological analysis of the lumbar spine showed that FXR deficiency reduced the bone formation rate as well as the trabecular bone volume and thickness. Moreover, tartrate-resistant acid phosphatase (TRACP) staining of the femurs revealed that both the osteoclast number and osteoclast surface were significantly increased in FXR^−/− mice compared with FXR^+/+ mice. At the cellular level, induction of alkaline phosphatase (ALP) activities was blunted in primary calvarial cells in FXR^−/− mice compared with FXR^+/+ mice in concert with a significant reduction in type I collagen a1(Col1a1), ALP, and runt-related transcription factor 2 (Runx2) gene expressions. Cultures of bone marrow–derived macrophages from FXR^−/− mice exhibited an increased number of osteoclast formations and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In female FXR^−/− mice, although bone mineral density (BMD) was not significantly different from that in FXR^+/+ mice, bone loss was accelerated after an ovariectomy compared with FXR^+/+ mice. In vitro, activation of FXR by bile acids (chenodeoxycholic acid [CDCA] or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced extracellular signal-regulated kinase (ERK) and β-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol (FOH 1%) diet marginally prevented ovariectomy (OVX)-induced bone loss and enhanced bone mass gain in growing C57BL/6J mice. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of the bone remodeling pathways; ie, bone formation and resorption. © 2013 American Society for Bone and Mineral Research.

Glucagon-like peptide-1 amide (GLP-1) and gastric inhibitory polypeptide (GIP) are incretin hormones regulating energy metabolism. GLP-1 and GIP combination is suggested as a promising therapeutic strategy for treatment of obesity and diabetes. However, the neuronal mechanisms are not yet investigated. In the present study, we investigated the role of central GLP-1 and GIP in regulation of body weight homeostasis. The effect of GLP-1 with GIP on food intake, body weight, locomotor activity were determined following intracerebroventricular (ICV) administration of GLP-1 and/or GIP in mice. ICV administration of low dose GLP-1 (0.3 nmol) and GIP (1 and 3 nmol) did not change food intake. However, ICV administration of higher doses GLP-1 (1 and 3 nmol) and GIP (6 nmol) significantly decreased food intake and body weight. To investigate the synergic effect of ICV GLP-1 and GIP, subeffective dose GLP-1 (0.3 nmol) and subeffective dose GIP (1 nmol) were chosen for further co-administration study. ICV co-administration of GLP-1 and GIP significantly decreased food intake, body weight and drinking. ICV co-administration of GLP-1 and GIP significantly increased neuronal activation and pro-opiomelanocortin (POMC) expression in hypothalamic arcuate nucleus. The neuronal activation and POMC expression were observed in two distinct neuronal populations. These results provide neuronal mechanisms supporting the development of GLP-1 and GIP combination therapeutics for treatment of obesity and diabetes.