Improved leptin sensitivity and increased soluble leptin receptor concentrations may underlie the additive effects of combining PYY [, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ] and exendin-4 on body weight lowering in diet-induced obese mice.

Objective: Co-treatment with long acting PYY and the GLP-1 receptor agonists has potential as an efficient obesity treatment. This study investigates whether the mechanisms behind additive reduction of food intake and weight loss depends on complementary effects in brain areas regulating food intake and if restoration of leptin sensitivity is involved. Methods: Diet-induced obese (DIO) mice were co-treated with PYY(3-36) and exendin-4 (Ex4, GLP-1R agonist) for 14 days using minipumps. Leptin responsiveness was evaluated by measuring food intake and body weight after leptin injection, and gene expression profile was investigated in various of brain regions and liver. Results: We show that weight loss associated with co-treatment of PYY(3-36) and Ex4 and Ex4 mono-treatment in DIO mice increased expression of several genes in area postrema (AP) known to be involved in appetite regulation and Cart, Pdyn, Bdnf and Klb were synergistically upregulated by the co-treatment. The upregulations were independent of weight loss, as shown by inclusion of a weight matched control. Moreover, PYY(3-36) and Ex4 co-treatment resulted in synergistically upregulated plasma concentrations of soluble leptin receptor (SLR) and improved sensitivity to exogenous leptin demonstrated by food intake lowering. Conclusion: The study results suggest that synergistic upregulation of appetite-regulating genes in AP and improved leptin sensitivity are important mediators for the additive weight loss resulting from PYY and Ex4 co-treatment.

Housing-temperature reveals energy intake counter-balances energy expenditure in normal-weight, but not diet-induced obese, male mice.

Most metabolic studies on mice are performed at room temperature, although under these conditions mice, unlike humans, spend considerable energy to maintain core temperature. Here, we characterize the impact of housing temperature on energy expenditure (EE), energy homeostasis and plasma concentrations of appetite- and glucoregulatory hormones in normal-weight and diet-induced obese (DIO) C57BL/6J mice fed chow or 45% high-fat-diet, respectively. Mice were housed for 33 days at 22, 25, 27.5, and 30 °C in an indirect-calorimetry-system. We show that energy expenditure increases linearly from 30 °C towards 22 °C and is ~30% higher at 22 °C in both mouse models. In normal-weight mice, food intake counter-balances EE. In contrast, DIO mice do not reduce food intake when EE is lowered. By end of study, mice at 30 °C, therefore, had higher body weight, fat mass and plasma glycerol and triglycerides than mice at 22 °C. Dysregulated counterbalancing in DIO mice may result from increased pleasure-based eating.

NPFF Decreases Activity of Human Arcuate NPY Neurons: A Study in Embryonic-Stem-Cell-Derived Model.

Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons.

Targeting the Gut in Obesity: Signals from the Inner Surface.

Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies a tremendous number of circulating signals that modulate the activity of appetite-regulating areas of the brain by either direct interaction or through the vagus nerve. Intestinally derived messengers are manifold and include absorbed nutrients, microbial metabolites, gut hormones and other enterokines, collectively comprising a fine-tuned signalling system to the brain. After a meal, nutrients directly interact with appetite-inhibiting areas of the brain and induce satiety. However, overall feeding behaviour also depends on secretion of gut hormones produced by highly specialized and sensitive enteroendocrine cells. Moreover, circulating microbial metabolites and their interactions with enteroendocrine cells further contribute to the regulation of feeding patterns. Current therapies exploiting the appetite-regulating properties of the gut are based on chemically modified versions of the gut hormone, glucagon-like peptide-1 (GLP-1) or on inhibitors of the primary GLP-1 inactivating enzyme, dipeptidyl peptidase-4 (DPP-4). The effectiveness of these approaches shows that that the gut is a promising target for therapeutic interventions to achieve significant weigh loss. We believe that increasing understanding of the functionality of the intestinal epithelium and new delivery systems will help develop selective and safe gut-based therapeutic strategies for improved obesity treatment in the future. Here, we provide an overview of the major homeostatic appetite-regulating signals generated by the intestinal epithelial cells and how these signals may be harnessed to treat obesity by pharmacological means.