Unravelling a unifying network for leptin and insulin interaction in the hypothalamus as a potential link between obesity and associated diseases. Genetherapeutic, pharmacological and nutritive interventions of crucial signalling pathways.

• Applicant: Dr. Alexander Tups
• Subject Area: Nutritional Sciences
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 243471766

• Final Report Year: 2017

Final Report Abstract

Metabolic inflammation in the central nervous system might be causative for the development of overnutrition-induced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Aim of this proposal was to identify whether hypothalamic inflammation may interrupt the central network of leptin and insulin signalling and thereby contribute to the development of obesity and type 2 diabetes. We established that nutritive and genetic inhibition of the central pro-inflammatory IκB kinase β (IKKβ)/nuclear factor-κB (NF-κB) pathway in diet-induced obese (DIO)- or leptin-deficient mice improves metabolic impairments. Genetic inhibition of the IKKβ/NF-κB signaling pathway in the arcuate nucleus, via specific adeno-associated virus serotype 2-mediated overexpression of IκBα, which inhibits NF-κB nuclear translocation, attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression (SOCS-3), suggesting that reversal of this process may enhance leptin signaling. One key question in metabolism research, which was also addressed in this proposal is whether leptin resistance is caused by hypothalamic inflammation, or whether hypothalamic inflammation is a consequence of leptin resistance because leptin acts also as a proinflammatory hormone. A loss of leptin sensitivity as determined by leptin’s ability to activate pSTAT3 in the arcuate nucleus occurred already within 24 hours of high fat feeding, well before body fat mass and circulating leptin levels increased, which coincides with the onset of hypothalamic inflammation suggesting this process is leading to leptin resistance rather than hyperleptinemia per se. Additionally, we also established that the evolutionary highly conserved WNT pathway plays a crucial role in the neuroendocrine regulation of body weight and exhibits a novel not yet identified leptin pathway.

Publications

• Central adiponectin acutely improves glucose tolerance in male mice. Endocrinology. 2014 May;155(5): 1806-16
  Koch, Christiane E.; Lowe, Chrishanthi; Legler, Karen; Benzler, Jonas; Boucsein, Alisa; Böttiger, Gregor; Grattan, David R.; Williams, Lynda M. & Tups, Alexander
  
• Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice. Endocrinology. 2014 Jul;155(7):2411-22
  Briggs, Dana I.; Lockie, Sarah H.; Benzler, Jonas; Wu, Qunli; Stark, Romana; Reichenbach, Alex; Hoy, Andrew J.; Lemus, Moyra B.; Coleman, Harold A.; Parkington, Helena C.; Tups, Alex & Andrews, Zane B.
  
• Phenotypic characterization of miR-92a-/- mice reveals an important function of miR-92a in skeletal development. PLoS One. 2014 Jun 30; 9(6): e101153
  Penzkofer, Daniela; Bonauer, Angelika; Fischer, Ariane; Tups, Alexander; Brandes, Ralf P.; Zeiher, Andreas M. & Dimmeler, Stefanie
  
• The development of diet-induced obesity and glucose intolerance in C57BL/6 mice on a high-fat diet consists of distinct phases. PLoS One. IF:3.2. 2014 Aug 29;9(8): e106159
  Williams, Lynda M.; Campbell, Fiona M.; Drew, Janice E.; Koch, Christiane; Hoggard, Nigel; Rees, William D.; Kamolrat, Torkamol; Thi Ngo, Ha; Steffensen, Inger-Lise; Gray, Stuart R. & Tups, Alexander
  
• Central inhibition of IKKβ/NF-κB signalling attenuates high fat diet-induced obesity and glucose intolerance. Diabetes. 2015 Jan 27 [Epub ahead of print]
  Benzler, Jonas; Ganjam, Goutham K.; Pretz, Dominik; Oelkrug, Rebecca; Koch, Christiane E.; Legler, Karen; Stöhr, Sigrid; Culmsee, Carsten; Williams, Lynda M. & Tups, Alexander
  
• Photoperoiodic and Diurnal Regulation of WNT Signalling in the Arcuate Nucleus of the Female Djungarian Hamster, Phodopus sungorus. Endocrinology. 2016 Feb;157(2):799-809
  Boucsein, Alisa; Benzler, Jonas; Hempp, Cindy; Stöhr, Sigrid; Helfer, Gisela & Tups, Alexander
  
• Hypothalamic WNT signalling and its role in energy balance regulation. J Neuroendocrinol. 2016
  Helfer, G. & Tups, A.
  
• Central Regulation of Glucose Homeostasis. Compr Physiol. 2017 Mar; 16;7(2):741-764
  Tups, Alexander; Benzler, Jonas; Sergi, Domenico; Ladyman, Sharon R. & Williams, Lynda M.
  
• Temporal and regional onset of leptin resistance in diet-induced obese mice. J Neuroendocrinol. 2017 May 6 (Epub ahead of print)
  Rizwan, M. Z.; Mehlitz, S.; Grattan, D. R. & Tups, A.