gw-3965 and Obesity

Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin β

Topics: 3T3 Cells; Adipocytes; Adipose Tissue; Animals; Apoptosis; Benzoates; Benzylamines; Cytokines; Diet, High-Fat; Fatty Liver; GTP-Binding Proteins; Inflammation; Insulin Resistance; Liver X Receptors; Lysosomes; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Protein Glutamine gamma Glutamyltransferase 2; Proto-Oncogene Proteins pp60(c-src); Signal Transduction; Transglutaminases; Triglycerides

Obesity is associated with many complications, including type 2 diabetes and painful neuropathy. There is no cure or prevention for obesity-induced pain, and the neurobiology underlying the onset of the disease is still obscure. In this study, we observe that western diet (WD)-fed mice developed early allodynia with an increase of ER stress markers in the sensory neurons of the dorsal root ganglia (DRG). Using cell-specific approaches, we demonstrate that neuronal liver X receptor (LXR) activation delays ER stress and allodynia in WD-fed mice. Our findings suggest that lipid-binding nuclear receptors expressed in the sensory neurons of the DRG play a role in the onset of obesity-induced hypersensitivity. The LXR and lipid-sensor pathways represent a research avenue to identify targets to prevent debilitating complications affecting the peripheral nerve system in obesity.

Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Animals; ATP Binding Cassette Transporter 1; Benzoates; Benzylamines; Diet, Western; Endoplasmic Reticulum Stress; Ganglia, Spinal; Hyperalgesia; Liver X Receptors; Male; Mice; Mice, Knockout; Obesity; Sensory Receptor Cells

To investigate the role of liver X receptor (LXR) in adipose tissue metabolism during obesity, ob/ob mice were treated for 5 weeks with the synthetic LXR agonist GW3965. MRI analysis revealed that pharmacological activation of LXR modified fat distribution by decreasing visceral (VS) fat and inversely increasing subcutaneous (SC) fat storage without affecting whole body fat content. This was concordant with opposite regulation by GW3965 of the lipolytic markers hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in the two fat depots; moreover, the expression of genes involved in lipogenesis was significantly induced in SC fat. Lipidomic analysis suggested that changes in lipid composition in response to GW3965 also varied between VS and SC fat. In both depots, the observed alteration in lipid composition indicated an overall change toward less lipotoxic lipids. Flow cytometry analysis showed decreased immune cell infiltration in adipose tissue of ob/ob mice in response to GW3965 treatment, which in VS fat mainly affected the macrophage population and in SC fat the lymphocyte population. In line with this, the expression and secretion of proinflammatory markers was decreased in both fat deposits with GW3965 treatment.

Topics: Adipogenesis; Adipose Tissue; Animals; Benzoates; Benzylamines; Body Fat Distribution; Female; Inflammation; Lipolysis; Liver X Receptors; Macrophages; Mice; Obesity; Orphan Nuclear Receptors

Obesity and nutrient homeostasis are linked by mechanisms that are not fully elucidated. Here we describe a secreted protein, adropin, encoded by a gene, Energy Homeostasis Associated (Enho), expressed in liver and brain. Liver Enho expression is regulated by nutrition: lean C57BL/6J mice fed high-fat diet (HFD) exhibited a rapid increase, while fasting reduced expression compared to controls. However, liver Enho expression declines with diet-induced obesity (DIO) associated with 3 months of HFD or with genetically induced obesity, suggesting an association with metabolic disorders in the obese state. In DIO mice, transgenic overexpression or systemic adropin treatment attenuated hepatosteatosis and insulin resistance independently of effects on adiposity or food intake. Adropin regulated expression of hepatic lipogenic genes and adipose tissue peroxisome proliferator-activated receptor gamma, a major regulator of lipogenesis. Adropin may therefore be a factor governing glucose and lipid homeostasis, which protects against hepatosteatosis and hyperinsulinemia associated with obesity.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Amino Acid Sequence; Animals; Base Sequence; Benzoates; Benzylamines; Blood Proteins; Cells, Cultured; DNA-Binding Proteins; Energy Metabolism; Fasting; Fatty Liver; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Lipid Metabolism; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Obesity; Orphan Nuclear Receptors; Peptides; Proteins; Receptors, Cytoplasmic and Nuclear; RNA Interference; RNA, Messenger; RNA, Small Interfering