Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis

The central nervous system (CNS) is capable of gathering information on the body’s nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus

Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production.

Insulin action in the central nervous system regulates energy homeostasis and glucose metabolism. To define the insulin-responsive neurons that mediate these effects, we generated mice with selective inactivation of the insulin receptor (IR) in either pro-opiomelanocortin (POMC)- or agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus. While neither POMC- nor AgRP-restricted IR knockout mice exhibited altered energy homeostasis, insulin failed to normally suppress hepatic glucose production during euglycemic-hyperinsulinemic clamps in AgRP-IR knockout (IR(DeltaAgRP)) mice. These mice also exhibited reduced insulin-stimulated hepatic interleukin-6 expression and increased hepatic expression of glucose-6-phosphatase. These results directly demonstrate that insulin action in POMC and AgRP cells is not required for steady-state regulation of food intake and body weight. However, insulin action specifically in AgRP-expressing neurons does play a critical role in controlling hepatic glucose production and may provide a target for the treatment of insulin resistance in type 2 diabetes

Higher plasma lipopolysaccharide concentrations are associated with less favorable phenotype in overweight/obese men

Lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria might be an inflammation trigger in adipose tissue. It has recently been proposed that there is a link between adipose tissue distribution and blood LPS. However, the number of studies on this topic is scarce, and further investigation in humans is required. In this study, we explored the association between plasma LPS concentrations and body fat distribution, as well as the biochemical parameters that may indicate the presence of metabolic disorders. Sixty-seven young adult men with body mass index of 26–35 kg/m2 were evaluated. Anthropometry, body composition and body fat distribution, blood pressure, energy expenditure, physical activity level, dietary intake, and biochemical parameters were assessed. Men with median plasma LPS ≥ 0.9 EU/mL presented higher sagittal abdominal diameter, trunk fat percentage, and android fat percentage, and mass, insulin and alanine aminotransferase concentrations, homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell dysfunction (HOMA-B) than those with lower plasma LPS. LPS correlated positively with the trunk fat percentage, and android fat percentage, and mass, insulin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase concentrations, as well as HOMA-IR and HOMA-B. Our results suggest that a higher plasma LPS concentration is associated with a less favorable phenotype as characterized by higher central adiposity, higher values of HOMA-IR, and beta cell function impairment in overweight/obese men

A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle

Over 40% of microRNAs (miRNAs) are located in introns of protein-coding genes, and many of these intronic miRNAs are co-regulated with their host genes(1,2). In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways(3,4). Therefore, we screened intronic miRNAs dysregulated in the livers of mouse models of obesity to identify previously uncharacterized protein-coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach revealed that expression of both the gene encoding ectodysplasin A (Eda), the causal gene in X-linked hypohidrotic ectodermal dysplasia (XLHED)(5), and its intronic miRNA, miR-676, was increased in the livers of obese mice. Moreover, hepatic EDA expression is increased in obese human subjects and reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. We also found that reducing miR-676 expression in db/db mice increases the expression of proteins involved in fatty acid oxidation and reduces the expression of inflammatory signaling components in the liver. Further, we found that Eda expression in mouse liver is controlled via PPAR gamma and RXR-alpha, increases in circulation under conditions of obesity, and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. In accordance with these findings, gain-and loss-of-function approaches reveal that liver-derived EDA regulates systemic glucose metabolism, suggesting that EDA is a hepatokine that can contribute to impaired skeletal muscle insulin sensitivity in obesity