Food contains three major macronutrients: carbohydrates, proteins, and fats. A balanced intake of these macronutrients is essential for the health and survival of organisms. Protein, a particularly important nutrient, is composed of essential amino acids (EAAs) and non-essential amino acids (NEAAs). EAAs cannot be synthesized by the body and therefore must be obtained from dietary sources, whereas NEAAs can be produced endogenously. Accordingly, animals must possess mechanisms to continuously monitor EAA levels and, when necessary, drive a specific appetite for EAAs or protein in order to maintain amino acid homeostasis. Our laboratory recently identified and characterized specific populations of gut and brain cells that detect and respond to EAA deprivation inDrosophila(Kim & Kanai et al., 2021; Kim & Lee et al., 2026). We are now investigating how these cells selectively promote the intake of protein or EAAs, rather than sugar or fat. In addition, we aim to identify and characterize the molecules and cells in the gut that directly detect individual EAAs and respond to their presence. We are extending this line of research to rodents.

Another major goal of our laboratory is to identify glucose sensors and glucose-sensing neurons and to define the physiological functions mediated by these molecules and cells. Glucose-sensing neurons respond to glucose or its metabolites, which serve as signaling cues to regulate neuronal activity. According to the glucostatic hypothesis proposed in 1953, feeding and related behaviors are regulated by brain neurons that detect changes in blood glucose levels (Mayer, 1953,NEJM). Although glucose-sensing neurons in the hypothalamus were identified more than a decade later using electrophysiological approaches (Oomura et al., 1964,Science), their physiological functions remained unclear until recently. Our laboratory identified and characterized a population of DH44-expressing glucose-excited neurons in theDrosophilabrain and demonstrated that they function as internal nutrient sensors that promote sugar intake (Parton et al., 2007,Nature; Levin, 2007,Cell Metabolism; Dus et al., 2015; Oh et al., 2021). In addition to these glucose-sensing neurons that regulate sugar consumption, we identified a pair of glucose-excited neurons that promote insulin release while simultaneously inhibiting glucagon release during hyperglycemia, thereby contributing to glucose homeostasis (Oh et al., 2019).

A central goal of our laboratory is to determine how distinct populations of glucose-excited and glucose-inhibited neurons in the brain and enteric nervous system contribute to specific aspects of feeding, metabolism, and homeostatic regulation.

Micronutrients are essential for the health and survival of organisms. Salt (sodium chloride) is a key micronutrient that contributes to a wide range of physiological processes. Until about a century ago, it was one of the most sought-after commodities, likely because humans were frequently deprived of sodium. Indeed, the human demand for salt helped establish trade routes and cities, provoked and financed wars, and shaped the governance of empires. Its importance was also reflected in religious symbolism. Despite extensive research on the taste perception of salt, we still know relatively little about whether animals can detect and respond to sodium independently of the taste system. Our laboratory recently demonstrated that animals can respond to sodium in the absence of taste input during periods of salt deprivation. UsingDrosophila, we identified a discrete population of enteric neurons, termed INSO (Internal Sodium Sensing) neurons, that function as taste-independent, postprandial sodium sensors that directly detect sodium ions and promote sodium intake (Kim et al., 2024). Intriguingly, these neurons extend dendrites to the anterior intestine and project axons to the brain. We therefore hypothesize that they detect ingested sodium in the intestine and relay this information to the brain, which in turn regulates salt appetite. This work on deprivation-induced sodium sensing by INSO neurons may provide insight into the strong drive for salt that has shaped both animal behavior and human history.

Vitamin C is another essential micronutrient for humans and for animals that cannot synthesize it endogenously. As an antioxidant, vitamin C plays an important role in scavenging reactive oxygen species (ROS), which are often generated under conditions of stress. We have asked whether fruit flies or mice develop a specific appetite for vitamin C and other antioxidants during stress. In nature, many animals seek out and consume particular plants enriched in nutrients or bioactive metabolites when they are sick, deprived, or in need of specific chemical compounds. This behavior is thought to help alleviate physiological stress or illness and has been termedself-medication. Self-medication has been observed in insects such as butterflies and fruit flies, as well as in primates such as chimpanzees. However, relatively few studies have addressed this phenomenon, and its underlying mechanisms remain poorly understood. Our laboratory is currently investigating whether fruit flies preferentially select antioxidants under stress and elucidating the mechanisms by which they are attracted to needed antioxidants, potentially through the action of interoceptive sensors distributed along the gut-brain axis (Hwang & Yang et al., 2025).

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and are characterized by progressive degeneration of the central nervous system. Aggregates of tau and alpha-synuclein (alpha-syn), respectively, are major pathological hallmarks of these diseases and are thought to play central roles in their etiologies. These proteins are also key drivers of a range of other tauopathies and synucleinopathies. In AD, tau progressively accumulates within neurons to form neurofibrillary tangles, leading to disruption of the cytoskeleton, neuronal death, and ultimately severe impairments in cognition, memory, and daily function. Similarly, PD is characterized by insoluble alpha-synuclein-containing inclusions, known as Lewy bodies, which selectively damage dopaminergic neurons in the substantia nigra. As a result of this neuronal loss, patients with PD develop motor symptoms including tremor, rigidity, and bradykinesia, as well as autonomic dysfunction and neuropsychiatric complications at later stages. In addition to these insoluble aggregates, soluble forms of tau and alpha-synuclein are also likely to contribute to the cell type-specific neurotoxicity observed in these disorders. Notably, the pathogenesis of PD, and possibly aspects of AD, has been proposed to begin in the gastrointestinal tract, where tau and alpha-synuclein aggregates may arise and subsequently spread to the brain through components of the gut-brain axis, including the vagus nerve. Importantly, there are currently no effective approved therapies that directly target and eliminate tau or alpha-synuclein aggregates, nor are there curative treatments for these diseases.

Our laboratory has recently initiated studies aimed at understanding the pathophysiology of these neurodegenerative disorders, particularly those that may originate in the gut through harmful interactions with the gut microbiome. Using rodent andDrosophilamodels, we are investigating the mechanisms by which Lewy bodies, and potentially neurofibrillary tangles, propagate to the brain through the gut-brain axis.