Browsing by Author "Basu, Rashmita"

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    Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet
    (Springer Nature, 2023-08-09) Lin, Li; Basu, Rashmita; Chatterjee, Debolina; Templin, Andrew T.; Flak, Jonathan N.; Johnson, Travis S.; Pharmacology and Toxicology, School of Medicine
    High-fat diet (HFD) is associated with Alzheimer's disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer's microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.
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    Hypothalamic Neural Circuits Regulating Energy Expenditure
    (Elsevier, 2025) Basu, Rashmita; Flak, Jonathan N.; Pharmacology and Toxicology, School of Medicine
    The hypothalamus plays a central role in regulating energy expenditure and maintaining energy homeostasis, crucial for an organism's survival. Located in the ventral diencephalon, it is a dynamic and adaptable brain region capable of rapid responses to environmental changes, exhibiting high anatomical and cellular plasticity and integrates a myriad of sensory information, internal physiological cues, and humoral factors to accurately interpret the nutritional state and adjust food intake, thermogenesis, and energy homeostasis. Key hypothalamic nuclei contain distinct neuron populations that respond to hormonal, nutrient, and neural inputs and communicate extensively with peripheral organs like the gastrointestinal tract, liver, pancreas, and adipose tissues to regulate energy production, storage, mobilization, and utilization. The hypothalamus has evolved to enhance energy storage for survival in famine and scarce environments but contribute to obesity in modern contexts of caloric abundance. It acts as a master regulator of whole-body energy homeostasis, rapidly adapting to ensure energy supplies for cellular functions. Understanding hypothalamic function, pertaining to energy expenditure, is crucial for developing targeted interventions to address metabolic disorders, offering new insights into the neural control of metabolic states and potential therapeutic strategies.
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    Identification of a Hypothalamic Neural System That Can Reduce Body Weight and Adipose Mass in Diet-Induced Obesity
    (2024-11) Basu, Rashmita; Flak, Jonathan N.; Linnemann, Amelia K.; Witczak, Carol A.; Sheets, Patrick L.; Jerde, Travis J.
    Dynamic hypothalamic circuits balance energy intake with expenditure to protect individuals from obesity. Lasting negative energy balance, however, triggers a compensatory decrease in energy expenditure, hindering progressive weight loss. While we understand some key players underlying energy balance, the detailed neural underpinnings remain unclear. Here I will delineate the functional efferent circuitry from the ventromedial hypothalamic nucleus (VMN) that facilitates weight loss and prevents rebound weight gain. VMN neurons have long been linked to a role in energy balance. Both vesicular communication by VMN steroidogenic factor 1 (SF1) neurons and pituitary adenylate cyclase activating peptide (PACAP) release from VMN neurons are essential for maintaining body weight and activating VMNSf1 neurons curbs diet-induced obesity without altering food intake. However, the exact pathway of this VMN signal is unclear because the VMN does not directly communicate with preganglionic sympathetic neurons, indicating signal transmission through an efferent node. Of the few brain sites they communicate with, VMNSf1 neurons sends the densest projections to the caudal preoptic area (POA) and the anterior bed nucleus of stria terminalis (BNST). Stimulating VMNPACAP axonal fibers in the caudal POA, but not anterior BNST, induced thermogenesis in brown and beige adipose tissues in both sexes of mice. To identify caudal POA populations in body weight regulation, I activated excitatory (glutamatergic) and inhibitory (GABAergic) caudal POA cells in diet-induced obese male mice and found that both glutamatergic and GABAergic caudal POA neurons can reduce diet-induced obesity through separate means. While there is intra-POA communication, my data supports efferent communication with separate downstream circuits by glutamate and GABA caudal POA cells in ameliorating diet-induced obesity. Because the POA and BNST are extremely complex regions with diverse functions, I then employed deep transfer learning to pinpoint obesity and diabetes risk-associated cell subsets in the POA and BNST. Using single nuclei RNA sequencing on >200,000 nuclei from both sexes of mice, I identified 6 specialized sets of caudal POA and BNST neuronal subtypes that increased in obese and glucose-intolerant mice on a high-fat diet. Targeting these newly identified pathways and neuron subtypes could lead to future obesity and diabetes therapeutics.
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    Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs
    (Elsevier, 2024) Basu, Rashmita; Elmendorf, Andrew J.; Lorentz, Betty; Mahler, Connor A.; Lazzaro, Olivia; App, Britany; Zhou, Shudi; Yamamoto, Yura; Suber, Mya; Wann, Jamie C.; Cheol Roh, Hyun; Sheets, Patrick L.; Johnson, Travis S.; Flak, Jonathan N.; Pharmacology and Toxicology, School of Medicine
    Objective: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established. Methods: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips. Results: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue. Conclusions: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.