Obesity affects 1/3 of adults, is a major contributor to type 2 diabetes, cardiovascular disease and other several cancers, and is the second leading cause of preventable death in the United States. Effective anti-obesity drugs are urgently needed as behavior therapy offers limited success and bariatric surgery, while effective, has serious adverse consequences. Support for basic science research has led to the discovery of a number of new chemical signals and their receptors that contribute to energy balance control. Those discoveries have driven the development of new drugs. It is clear however, that energy balance control is multi-determined, with multiple signals, receptors, and regions of the brain operating with some degree of redundancy to insure that adequate energy is available for survival and reproduction. For this reason, it is important to be skeptical about whether emerging treatments will be efficacious in treating obesity. We argue that greater progress in developing effective anti-obesity drug therapies will result from research aimed at identifying the neurons and the neural circuits that are common to mediating the food intake inhibitory effects of different physiological signals, such as the adipose tissue-derived hormone leptin and gastrointestinal (GI) satiation signals. Our recent work shows that medial, nucleus solitarious (mNTS) leptin signaling amplifies the food intake inhibitory effects of various GI satiation signals. Complementing these results are data showing that targeted reduction in endogenous mNTS leptin receptor (LepRb) signaling (RNA interference [RNA-i]-mediated) triggers hyperphagia and weight gain, in part, via reduction in the food intake suppressive effect of GI satiation signals. These data establish that mNTS leptin signaling is physiologically relevant to the control of food intake and body weight. Recent pilot data complement these findings by showing that increased mNTS leptin signaling reduces the rewarding value of food and suppresses learned motivated behaviors directed towards food procurement.
Aim I experiments use double immunohistochemistry to address whether mNTS LepRb+ neurons directly project to midbrain/forebrain nuclei associated with food intake control and assess the functional contributions of these projections to nucleus accumbens by measuring neural activity and dopamine release triggered by cues- associated with food reward and to the lateral hypothalamus by assessing intake behavioral and food reward effects of mNTS leptin.
Aim II experiments employ behavioral, pharmacological, and genetic (RNA-i) strategies and neurophysiological experiments targeting LepRbEYFP neurons to determine whether descending hypothalamic oxytocin (OT) and orexin (ORX) projections to mNTS influence food intake by amplifying (ORX) or attenuating (OT) the mNTS processing of GI signals, LepRb signals or their combination. A variety of preliminary results support the hypotheses under investigation.

Public Health Relevance

Basic scientists make discoveries that suggest that stimulating one brain chemical system will reduce food intake, and then the pharmaceutical industry develops such a drug to treat obesity. The problem with this approach, and the drugs now on the market, is that because the control of food intake is so important for survival many different brain chemical systems work in parallel to insure that food intake is not reduced. A novel approach is taken here, we think that more progress in finding effective anti-obesity drug treatments will arise when scientists define the particular brain cells that are commonly activated by food in the stomach and intestine and by leptin, the hormone made by fat tissue, because food intake is more effectively reduced by their combination than by either one alone.

National Institute of Health (NIH)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Yanovski, Susan Z
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University of Pennsylvania
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Kanoski, S E; Ong, Z Y; Fortin, S M et al. (2015) Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms. Diabetes Obes Metab 17:285-93
Ozek, Ceren; Kanoski, Scott E; Zhang, Zhong-Yin et al. (2014) Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling. J Biol Chem 289:31682-92
Kanoski, Scott E; Alhadeff, Amber L; Fortin, Samantha M et al. (2014) Leptin signaling in the medial nucleus tractus solitarius reduces food seeking and willingness to work for food. Neuropsychopharmacology 39:605-13
Alhadeff, Amber L; Baird, John-Paul; Swick, Jennifer C et al. (2014) Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed. Neuropsychopharmacology 39:2233-43
Kanoski, Scott E; Fortin, Samantha M; Ricks, Katie M et al. (2013) Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biol Psychiatry 73:915-23
Grill, Harvey J (2010) Leptin and the systems neuroscience of meal size control. Front Neuroendocrinol 31:61-78
Hayes, Matthew R; Skibicka, Karolina P; Leichner, Theresa M et al. (2010) Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab 11:77-83
Faulconbridge, Lucy F; Grill, Harvey J; Kaplan, Joel M et al. (2008) Caudal brainstem delivery of ghrelin induces fos expression in the nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus. Brain Res 1218:151-7
Nautiyal, Katherine M; Dailey, Megan; Brito, Nilton et al. (2008) Energetic responses to cold temperatures in rats lacking forebrain-caudal brain stem connections. Am J Physiol Regul Integr Comp Physiol 295:R789-98
Huo, Lihong; Maeng, Lisa; Bjorbaek, Christian et al. (2007) Leptin and the control of food intake: neurons in the nucleus of the solitary tract are activated by both gastric distension and leptin. Endocrinology 148:2189-97

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