About

Nishanth E. Sunny is an Associate Professor in the Department of Animal & Avian Sciences at the University of Maryland. His research focuses on the biochemistry of metabolism, particularly how metabolic pathways undergo remodeling during growth, development, and in the context of metabolic diseases such as obesity, fatty liver, and type II diabetes mellitus (T2DM). His lab investigates the critical pathways involved in metabolic regulation, with a specific interest in understanding how hepatic mitochondria integrate substrate flux, oxidative phosphorylation, ATP synthesis, and inflammation to maintain normal cell function. Strategies or agents targeting mitochondrial dysfunction are explored as potential treatments for metabolic diseases and to enhance growth and development. Dr. Sunny employs various in vitro cell culture systems and in vivo animal models, including diet-induced/transgenic mice and chicken embryo/neonatal chick models, to study mitochondrial function and metabolic transitions during growth. His research utilizes stable isotope-based techniques for metabolic flux analysis, targeted metabolomics, mass spectrometry, and nuclear magnetic resonance (NMR) approaches, combined with molecular biology methods, to profile tissue-specific metabolism and identify shared metabolic defects contributing to metabolic disorders.

Research topics

• Endocrinology
• Internal medicine
• Medicine
• Biology
• Biochemistry
• Chemistry
• Physiology

Selected publications

• Induction of Fructose Mediated De Novo Lipogenesis Coexists with the Upregulation of Mitochondrial Oxidative Function in Mice Livers

  Journal of Nutrition · 2025-05-05 · 4 citations

  articleOpen accessSenior authorCorresponding

  BACKGROUND: Dysfunctional mitochondrial metabolism and sustained de novo lipogenesis (DNL) are characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD), a comorbidity of obesity and type 2 diabetes. Fructose, a common sweetener and a potent inducer of lipogenesis, contributes to the etiology of MASLD. OBJECTIVES: Our goal was to determine whether higher rates of DNL, through its biochemical relationships with mitochondria, can contribute to dysfunctional induction of oxidative networks in the liver. METHODS: Male C57BL/6JN mice were given a low-fat (10% fat kcal, 49.9% corn starch kcal), high-fat (HF; 60% fat kcal), or HF/high-fructose diet (HF/HFr; 25% fat kcal, 34.9% fructose kcal) for 24 wk. In a follow-up study, mice on normal feed pellets were provided either 30% fructose in drinking water (FW) to induce hepatic DNL or regular water (NW) for 14 d. Hepatic mitochondria and liver tissue were used to determine oxygen consumption, reactive oxygen species (ROS) generation, tricarboxylic acid (TCA) cycle activity, and gene/protein expression profiles. RESULTS: Hepatic steatosis remained similar between HF and HF/HFr fed mice livers. However, lipogenic and lipid oxidation gene expression profiles and the induction of TCA cycle metabolism were all higher (P ≤ 0.05) in HF/HFr livers. Under fed conditions, the upregulation of DNL in FW livers occurred in concert with higher mitochondrial oxygen consumption (basal; 1.7 ± 0.21 compared with 3.3 ± 0.14 nmoles/min, P ≤ 0.05), higher ROS (0.87 ± 0.09 compared with 1.25 ± 0.12 μM, P ≤ 0.05) and higher flux through TCA cycle components P ≤0.05. Furthermore, TCA cycle activity and lipid oxidation remained higher during fasting in the FW livers P ≤ 0.05. CONCLUSIONS: Our results show that fructose administration to mice led to the concurrent induction of mitochondrial oxidative networks and DNL in the liver. Sustained induction of both DNL and mitochondrial oxidative function could accelerate cellular stress and metabolic dysfunction during MASLD.

  PublisherDOI

• In vivo Imaging of Dysregulated β-Oxidation in a Diet-Induced Model of MASLD with [D15]octanoate

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of adults in the US. Disease can progress to more severe forms and eventually death. Current diagnosis by liver biopsy is limited by sampling error and morbidity risk. Development of improved diagnostics is required. Goal(s): Development of a minimally invasive method based on deuterium metabolic imaging (DMI) may improve MASLD diagnostics. Approach: Imaging deuterated water (HDO) production from [D15]octanoate metabolism to assess β-oxidative capacity in a MASLD mouse model. Results: [D15]octanoate DMI generated metabolic maps of β-oxidation and demonstrated reduced β-oxidative efficiency that correlated with clinically relevant assays for MASLD. Impact: Imaging HDO production from [D15]octanoate oxidation can detect organ specific metabolism and may lead to a novel clinical method for staging MASLD in a minimally invasive manner. [D15]octanoate DMI needs to be tested in humans to assess clinical capability.

  PublisherDOI

• Comparative Analysis of Fat Sources in Infant Formulas and Their Metabolic Consequences in the Development of Non-Alcoholic Fatty Liver Disease in a Pediatric Pig Model

  Current Developments in Nutrition · 2025-05-01

  articleOpen access
  PublisherDOI

• Fluxomics combined with shotgun proteomics reveals a differential response of bovine kidney cells to extracellular palmitic and α-linolenic acid

  Physiological Genomics · 2025-02-07 · 3 citations

  articleOpen access

  knockdown requires extracellular amino acids to support TCA cycle intermediates. Cells incubated in palmitic acid demonstrated dependency of pyruvate and amino acids as substrates for the TCA cycle. Exposure to α-linolenic acid reduces the dependency of pyruvate as a substrate likely because carbon from α-linolenic acid can be used to supply TCA cycle intermediates whereas palmitic acid carbon is not used.

  PublisherDOI

• Concurrent increase in fatty acid oxidation and fatty acid synthesis: a unique metabolic state in a pig model of pediatric steatotic liver disease

  American Journal of Physiology-Endocrinology and Metabolism · 2025-11-18

  articleOpen access

  We identify a distinct metabolic state in neonatal pigs with SLD. Contrary to the prevailing paradigm, disease development and progression to the more severe steatohepatitis occur despite enhanced hepatic fatty acid oxidation and the concurrent upregulation of both lipolytic and lipogenic gene expression. This paradoxical metabolic state, where increased fatty acid oxidation fails to prevent progressive steatosis, provides new insights into early-life SLD pathophysiology.

  PublisherDOI

• Adaptations in Tricarboxylic Acid Cycle and Branched-Chain Amino Acid Degradation in Embryonic and Neonatal Chicken Muscle

  Physiology · 2025-05-01

  articleSenior author

  A dramatic metabolic switch from lipid oxidation to lipid accumulation is a characteristic feature of the embryonic-to-neonatal transition in chickens. While this metabolic switch is well characterized in the liver, it is unclear how muscle mitochondrial energetics adapt during embryonic-to-neonatal transition. Further, emerging evidence suggests a tight correlation between changes in lipid metabolism and branched-chain amino acid (BCAA) metabolism. We hypothesized that the activity of the tricarboxylic acid (TCA) cycle in the muscle will progressively increase during the embryonic-to-neonatal transition and that this rate of increase will be positively correlated with rates of BCAA degradation. Leg muscles were dissected and flash frozen in liquid nitrogen from broiler (Strain: Ross 708; flock age 25-30 wks.) embryonic (E) days 9, 11, 13, 15, and 18, the day of hatch, and 2- and 4 days post-hatch (PH). Gas-chromatography mass-spectrometry-based targeted metabolomics were utilized to determine tissue levels of TCA cycle intermediates, essential and non-essential amino acids, beta-hydroxybutyrate, and the corresponding keto-acids of BCAAs. Consistent with the higher rates of lipid oxidation during embryonic stages, beta-hydroxybutyrate (µg/g muscle ± SEM) was significantly higher in embryonic muscles vs. their post-hatch counterparts (E18; 847±35 vs. PH2; 87±6, p ≤ 0.001). On the contrary, several of the TCA cycle intermediates in the muscle (µg/g muscle ± SEM) were significantly higher during the post-hatch stages compared to their embryonic counterparts (e.g., Succinate; E18; 95±16 vs. PH2; 262±41, p ≤ 0.001; Malate; E18; 110±11 vs. PH2; 309±18, p ≤ 0.001). All three keto-acid intermediates (µg/g muscle ± SEM) of BCAA transamination were higher in the embryonic muscle compared to their post-hatch counterparts (e.g., α-ketoisovaleric acid of valine; KIV; E18; 4.52±0.55 vs. PH2; 1.29±0.17, p ≤ 0.01). The significantly lower keto-acid to BCAA ratios in the post-hatch muscles (e.g., KIV/Valine; E18; 0.022±0.003 vs. PH2; 0.005±0.001, p ≤ 0.001) further highlighted the decreasing rates of BCAA degradation with embryonic-to-neonatal transition. More interestingly, the BCAA keto-acids in the muscle showed a negative correlation with several intermediates of the TCA cycle (e.g., Succinate vs. KIV; r (55) = -0.56, p ≤ 0.001) suggesting a possible crosstalk between BCAA degradation and mitochondrial TCA cycle metabolism. In conclusion, these results demonstrate that an induction in the activity of TCA cycle metabolism coexists with the downregulation of BCAA degradation during the embryonic-to-neonatal transition in chicken muscle. Identifying whether the changes in BCAA degradation can modulate TCA cycle activity will provide avenues to nutritionally or molecularly enhance and optimize muscle mitochondrial function. AFRI-USDA-NIFA, Grant # 2021-67015-33387 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• Medium-Chain Fatty Acid Feeding Reduces Oxidation and Causes Panacinar Steatosis in Livers of Neonatal Pigs

  Journal of Nutrition · 2024-01-20 · 6 citations

  article
  PublisherDOI

• Detecting altered hepatic lipid oxidation by MRI in an animal model of MASLD

  Cell Reports Medicine · 2024-09-01 · 8 citations

  articleOpen access

  ]octanoate to deuterated water and detection with deuterium magnetic resonance methods. Perfused livers from a mouse model of MASLD reveal dysregulated hepatic β-oxidation, findings that corroborate in vivo imaging. The high-fat-diet-induced MASLD mouse studies indicate that decreased β-oxidative efficiency in the fatty liver could serve as an indicator of MASLD progression. Furthermore, our method provides a clinically translatable imaging approach for determining hepatic β-oxidation efficiency.

  PublisherDOI

• Autosomal-dominant macular dystrophy linked to a chromosome 17 tandem duplication

  JCI Insight · 2024-10-22

  articleOpen access

  Hereditary macular dystrophies (HMDs) are a genetically diverse group of disorders that cause central vision loss due to photoreceptor and retinal pigment epithelium (RPE) damage. We investigated a family with a presumed novel autosomal-dominant HMD characterized by faint, hypopigmented RPE changes involving the central retina. Genome and RNA sequencing identified the disease-causing variant to be a 560 kb tandem duplication on chromosome 17 [NC_000017.10 (hg19): g.4012590_4573014dup], which led to the formation of a novel ZZEF1-ALOX15 fusion gene, which upregulates ALOX15. ALOX15 encodes a lipoxygenase involved in polyunsaturated fatty acid metabolism. Functional studies showed retinal disorganization and photoreceptor and RPE damage following electroporation of the chimera transcript in mouse retina. Photoreceptor damage also occurred following electroporation with a native ALOX15 transcript but not with a near-null ALOX15 transcript. Affected patients' lymphoblasts demonstrated lower levels of ALOX15 substrates and an accumulation of neutral lipids. We implicated the fusion gene as the cause of this family's HMD, due to mislocalization and overexpression of ALOX15, driven by the ZZEF1 promoter. To our knowledge, this is the first reported instance of a fusion gene leading to HMD or inherited retinal dystrophy, highlighting the need to prioritize duplication analysis in unsolved retinal dystrophies.

  PublisherDOI

• Long-chain fatty acids mediate hepatic metabolic flux in preruminating dairy calves fed flaxseed oil, high oleic soybean oil, or milk fat

  Journal of Dairy Science · 2024-06-13 · 3 citations

  articleOpen access

  Nutrition and physiological state affect hepatic metabolism. Our objective was to determine if feeding flaxseed oil (∼50% C18:3n-3 cis), high oleic soybean oil (∼70% C18:1 cis-9), or milk fat (∼50% C16:0) alters hepatic expression of PC, PCK1, and PCK2 and the flow of carbons from propionate and pyruvate into the TCA cycle in preruminating calves. Male Holstein calves (n = 40) were assigned to a diet of skim milk with either: 3% milk fat (MF; n = 8), 3% flaxseed oil (Flax; n = 8), 3% high oleic soybean oil (HOSO; n = 8), 1.5% MF + 1.5% high oleic soybean oil (MF-HOSO; n = 8), or 1.5% MF + 1.5% flaxseed oil (MF-Flax; n = 8) from d 14 to d 21 postnatal. At d 21 postnatal, a liver biopsy was taken for gene expression and metabolic flux analysis. Liver explants were incubated in [U-13C] propionate and [U-13C] pyruvate to trace carbon flux through TCA cycle intermediates or with [U-14C] lactate, [1-14C] palmitic acid, or [2-14C] propionate to quantify substrate oxidation to CO2 and acid soluble products. Compared with other treatments, plasma C18:3n-3 cis was 10 times higher and C18:1 cis-9 was 3 times lower in both flax (Flax and MF-Flax) treatments. PC, PCK1, and PCK2 expression and flux of [U-13C] pyruvate as well as [U-13C] propionate were not different between treatments. PC expression was negatively correlated with the enrichment of citrate M+5 and malate M+3, and PCK2 was negatively correlated with citrate M+5, suggesting that when expression of these enzymes is increased, carbon from pyruvate enters the TCA cycle via PC mediated carboxylation, and then OAA is converted to phosphoenolpyruvate via PCK2. Acid soluble product formation and PC expression were reduced in HOSO (MF-HOSO and HOSO) treatments compared with flax (MF-Flax and Flax), indicating that fatty acids regulate PC expression and carbon flux, but that fatty acid flux control points are not connected to PC, PCK1, or PCK2. In conclusion, fatty acids regulate hepatic expression of PC, PCK1, and PCK2, and carbon flux, but the point of control is distinct.

  PublisherOA PDFDOI

Recent grants

• Metabolic Origins of Nonalcoholic Steatohepatitis

  NIH · $1.8M · 2017–2024

Frequent coauthors

• Shawn C. Burgess

  HumanN (United States)

  37 shared

• Kenneth Cusi

  29 shared

• Santhosh Satapati

  Instituto Superior Politécnico Metropolitano de Angola

  27 shared

• TianTeng He

  21 shared

• Chaitra Surugihalli

  18 shared

• Xiaorong Fu

  China-US (Henan) Hormel Cancer Institute

  16 shared

• Vaishna Muralidaran

  16 shared

• Srilaxmi Kalavalapalli

  Florida College

  14 shared