title: Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans.
abstract: Treating obesity has proven to be an intractable challenge, in part, due to the difficulty of maintaining reduced weight. In our previous studies of in-patient obese subjects, we have shown that leptin repletion following a 10% or greater weight loss reduces many of the metabolic (decreased energy expenditure, sympathetic nervous system tone, and bioactive thyroid hormones) and behavioral (delayed satiation) changes that favor regain of lost weight. FMRI studies of these same subjects have shown leptin-sensitive increases in activation of the right hypothalamus and reduced activation of the cingulate, medial frontal and parahippocampal gryi, following weight loss, in response to food stimuli. In the present study, we expanded our cohort of in-patient subjects and employed psychophysiological interaction (PPI) analysis to examine changes in the functional connectivity of the right hypothalamus. During reduced-weight maintenance with placebo injections, the functional connectivity of the hypothalamus increased with visual areas and the dorsal anterior cingulate (dorsal ACC) in response to food cues, consistent with higher sensitivity to food. During reduced-weight maintenance with leptin injections, however, the functional connectivity of the right hypothalamus increased with the mid-insula and the central and parietal operculae, suggesting increased coupling with the interoceptive system, and decreased with the orbital frontal cortex, frontal pole and the dorsal ACC, suggesting a down-regulated sensitivity to food. These findings reveal neural mechanisms that may underlie observed changes in sensitivity to food cues in the obese population during reduced-weight maintenance and leptin repletion.
authors.affiliation: Department of Neuroscience, Columbia University Medical Center/New York Presbyterian Medical Center, New York, NY, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hinkle
authors.forename: Michael
authors.initials: M
authors.lastname: Cordell
authors.forename: Rudy
authors.initials: R
authors.lastname: Leibel
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenbaum
authors.forename: Joy
authors.initials: J
authors.lastname: Hirsch
mesh_terms: D000328:Adult; D001931:Brain Mapping; D004032:Diet; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects*; D007279:Injections, Subcutaneous; D020738:Leptin / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D012527:Satiation / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D020738:Leptin
references.citation: Am J Clin Nutr. 2005 Jul;82(1 Suppl):222S-225S
references.pmid: 16002825
references.citation: Physiol Behav. 2012 Feb 28;105(4):1028-34
references.pmid: 22155218
references.citation: Obesity (Silver Spring). 2010 Feb;18(2):254-60
references.pmid: 19629052
references.citation: Brain Lang. 2013 Nov;127(2):222-9
references.pmid: 22889467
references.citation: JAMA. 1999 Oct 27;282(16):1568-75
references.pmid: 10546697
references.citation: J Clin Invest. 2005 Dec;115(12):3579-86
references.pmid: 16322796
references.citation: Am J Clin Nutr. 2008 Oct;88(4):906-12
references.pmid: 18842775
references.citation: Eur J Neurosci. 2004 Sep;20(5):1411-8
references.pmid: 15341613
references.citation: Physiol Behav. 2011 Sep 26;104(4):608-12
references.pmid: 21496461
references.citation: Cereb Cortex. 2009 Oct;19(10):2240-7
references.pmid: 19131436
references.citation: Nat Neurosci. 2012 Jun 24;15(8):1108-10
references.pmid: 22729177
references.citation: Am J Physiol Regul Integr Comp Physiol. 2010 Jan;298(1):R79-88
references.pmid: 19889869
references.citation: Cereb Cortex. 2003 Oct;13(10):1064-71
references.pmid: 12967923
references.citation: Cell Metab. 2008 Feb;7(2):179-85
references.pmid: 18249177
references.citation: Int J Obes Relat Metab Disord. 1998 Jan;22(1):14-22
references.pmid: 9481595
references.citation: Neuroimage. 2011 Jun 15;56(4):2157-72
references.pmid: 21459151
references.citation: Neuroimage. 2012 Jul 16;61(4):1129-42
references.pmid: 22440648
references.citation: J Clin Invest. 2002 Oct;110(8):1093-103
references.pmid: 12393845
references.citation: Neuroreport. 1999 Jan 18;10(1):7-14
references.pmid: 10094124
references.citation: Am J Clin Nutr. 2001 Oct;74(4):426-34
references.pmid: 11566639
references.citation: Soc Cogn Affect Neurosci. 2012 Jun;7(5):604-9
references.pmid: 22569188
references.citation: Neuroimage. 2011 Jan 1;54(1):653-60
references.pmid: 20659568
references.citation: Am J Clin Nutr. 1997 Aug;66(2):239-46
references.pmid: 9250100
references.citation: Neuroimage. 1997 Oct;6(3):218-29
references.pmid: 9344826
references.citation: Clin Cornerstone. 2007;8(3):29-37
references.pmid: 18452840
references.citation: Arch Gen Psychiatry. 2011 Aug;68(8):808-16
references.pmid: 21464344
references.citation: Neuroimage. 2012 Sep;62(3):1717-25
references.pmid: 22728149
references.citation: Obes Rev. 2011 Jan;12(1):50-61
references.pmid: 20059703
references.citation: Am J Clin Nutr. 2003 Apr;77(4):771-6
references.pmid: 12663271
references.citation: PLoS One. 2012;7(2):e31089
references.pmid: 22319604
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4569-74
references.pmid: 10200303
references.citation: Neuroscience. 2005;135(3):915-25
references.pmid: 16154276
references.citation: Neuron. 2006 Sep 21;51(6):811-22
references.pmid: 16982425
references.citation: J Clin Invest. 2008 Jul;118(7):2583-91
references.pmid: 18568078
references.citation: Neuroimage. 2004;23 Suppl 1:S208-19
references.pmid: 15501092
references.citation: Annu Rev Nutr. 2001;21:323-41
references.pmid: 11375440
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1259-66
references.pmid: 21917907
references.citation: Prog Neurobiol. 2008 Nov;86(3):216-44
references.pmid: 18824074
references.citation: Eur J Endocrinol. 2003 Jun;148(6):649-55
references.pmid: 12773137
references.citation: Brain Res. 2010 Sep 2;1350:95-102
references.pmid: 20595050
references.citation: Nat Neurosci. 2001 Jan;4(1):95-102
references.pmid: 11135651
references.citation: Arch Intern Med. 2005 Nov 14;165(20):2430
references.pmid: 16287779
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Aug;283(2):R281-3
references.pmid: 12121837
references.citation: J Clin Endocrinol Metab. 2011 Aug;96(8):E1283-7
references.pmid: 21593110
references.citation: Hum Brain Mapp. 2013 Nov;34(11):2944-58
references.pmid: 22696421
references.citation: Am J Clin Nutr. 2012 Feb;95(2):309-17
references.pmid: 22237063
references.citation: Rev Neurol (Paris). 2012 Aug-Sep;168(8-9):569-75
references.pmid: 22902172
references.citation: Brain Res Bull. 2009 Aug 14;79(6):388-95
references.pmid: 19467298
references.citation: Am J Physiol Regul Integr Comp Physiol. 2003 Jul;285(1):R183-92
references.pmid: 12609816
references.citation: Neuroimage. 2011 Mar 1;55(1):296-303
references.pmid: 21111829
references.citation: Am J Clin Nutr. 2007 Oct;86(4):965-71
references.pmid: 17921372
references.citation: Neuron. 2006 Sep 21;51(6):801-10
references.pmid: 16982424
references.citation: Eur J Neurosci. 2009 Aug;30(3):415-30
references.pmid: 19614751
references.citation: J Comp Neurol. 2010 Feb 15;518(4):459-76
references.pmid: 20017211