Mechanisms for oral-hypothalamic sugar detection

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of Pennsylvania $149,766 on August 17, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate mechanisms by which hypothalamic neurons differentiate between caloric sugars and non-caloric sweeteners.

The research combines intraoral cannulation with in vivo fiber photometry to examine how orally-infused sugars and sweeteners affect hypothalamic nuclei critical for food intake regulation. Preliminary findings demonstrate that hypothalamic agouti-related protein (AGRP)-expressing neurons are strongly modulated by oral glucose detection compared to saccharin, an effect mediated by oral sodium-glucose cotransporter 1 (SGLT1), which transports glucose but not sweeteners into taste cells. The proposed work investigates mechanisms by which oral glucose versus sweeteners produce divergent effects on AGRP neurons, including the roles of glucokinase and ATP-sensitive potassium channels in glucose metabolism within taste cells.

The award is classified as a Project Grant. Performance occurs in Philadelphia, Pennsylvania, with a period of performance extending through July 31, 2027.

Abstract

Mechanisms for oral-hypothalamic sugar detection the primary goal of this proposal is to investigate the peripheral and central mechanisms that enable key hypothalamic feeding neurons to differentiate between oral sugar and non-caloric sweeteners. Obesity is a significant health crisis, contributing to life-threatening metabolic conditions and posing a major economic burden. IT is closely linked to the overconsumption of highly palatable, sugar-rich foods. Traditionally, sweet taste (sugar or sweeteners) is thought to be detected in the mouth by the receptors T1R2+T1R3. These signals are subsequently sent to the brain via the rostral nucleus tractus solitarius (rnts) in the brainstem to promote food consumption. However, IT remains unclear whether orosensory signals distinguish between caloric sugars and non-caloric artificial sweeteners, and how this information is subsequently transmitted to the brain. To address this GAP, i developed a strategy that combines intraoral cannulation with in vivo fiber photometry. This allows US to carefully examine how orally-infused sugars and sweeteners affect hypothalamic nuclei critical for food intake regulation. My preliminary data demonstrate that hypothalamic agouti-related protein (agrp)- expressing neurons are strongly modulated by the detection of intraoral glucose (a caloric sugar) compared to saccharin (a non-caloric sweetener). This effect is mediated by oral sodium-glucose cotransporter 1 (SGLT1), which transports glucose, but not sweeteners, into taste cells. Therefore, the proposed research will investigate the mechanisms by which oral glucose VS. Sweeteners produce divergent effects on agrp neurons. In addition to sweet taste receptors, taste cells also contain mechanisms for glucose metabolism. These include glucokinase (GCK), an enzyme necessary for glucose metabolism and ATP production, as well as ATP-sensitive potassium channels (katp), which can depolarize taste cells. The first aim of this project will utilize genetic knockout of katp and lentiviral short hairpin RNA knockdown of GCK in combination with fiber photometry to determine whether these metabolic components are necessary for the effect of oral glucose on agrp neurons. Once taste stimuli are processed by taste cells, signals are then conveyed via cranial nerves to the rnts, first central taste relay. Excitingly, my preliminary data suggest that glucose-activated rnts neurons indirectly communicate with agrp neurons. Thus, my second aim will use two-photon single-cell imaging to determine whether distinct neuronal subpopulations in the rnts respond to oral sugar versus artificial sweeteners. The results of these experiments will reveal how glucose-specific signals are transmitted to agrp neurons via signaling from the rnts. Ultimately, this work will deepen our understanding of the peripheral and central circuits involved in sugar detection. This will advance our knowledge of the neurobiological mechanisms behind sugar consumption and potentially generate better therapeutic interventions for obesity and other feeding disorders.