Biology subjects

Potthoff, M. J.

Publications and source records attributed to Potthoff, M. J..

7 recordsLinked to original sources

bioRxiv2026

Method to Identify Liver-to-Brain Region-Specific Crosstalk Using TurboID

Endocrine crosstalk between the liver and the brain regulates systemic energy homeostasis. However, this communication has not been comprehensively evaluated because identification of liver-derived proteins, or hepatokines, is difficult to define using bulk serum proteomics alone. To overcome this problem, we applied hepatocyte-restricted endoplasmic-reticulum targeted TurboID (ER-TurboID) in vivo and recovered biotinylated, liver-secretion competent proteins directly from specific brain regions, including the hypothalamus and hindbrain (nucleus of the solitary tract (NTS) and area postrema (AP)). Compared with AAV8-Null transduced controls, TurboID-expressing animals showed 3- to 21-fold enrichment of liver-expressed and predicted liver-secreted proteins among brain regions, with 81 canonical liver-secretome proteins, including multiple carboxylesterase (CES) family members. These results establish a method to identify novel secreted factors from peripheral tissues that can potentially act on specific brain regions.

biochemistry↗

bioRxiv2025

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging elevates BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved age-related BAT senescence, metabolic decline, and cognitive dysfunction. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide bioactivity and metabolism in the context of aging. HighlightsO_LIAging elevates general protein S-nitrosylation while downregulating ADH5 expression in BAT. C_LIO_LILoss of thermogenic adipose tissue ADH5 accelerates BAT senescence and exacerbates aging-associated metabolic and cognitive dysfunctions. C_LIO_LIDisruption of HSF1-activated Adh5 in BAT contributes to aging-associated metabolic and cognitive impairments. C_LIO_LIPharmacological targeting of BAT HSF1 alleviates aging-related BAT senescent and systemic declines. C_LI

physiology↗

bioRxiv2023

ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially via upregulation of FGF21. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue (WAT). Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis by activating amino acid metabolism in BAT in a FGF21-independent manner. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/531964v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1d2c3fdorg.highwire.dtl.DTLVardef@414f5forg.highwire.dtl.DTLVardef@1c1fa9eorg.highwire.dtl.DTLVardef@2cc815_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets

Glucagon-like peptide-1 receptor (GLP-1R) agonists and fibroblast growth factor 21 (FGF21) confer similar metabolic benefits. Studies report that GLP-1RA induce FGF21. Here, we investigated the mechanisms engaged by the GLP-1R agonist liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. We show that liraglutide increases FGF21 levels via neuronal GLP-1R activation. We also demonstrate that lack of liver Fgf21 expression confers partial resistance to liraglutide-induced weight loss. Since FGF21 reduces carbohydrate intake, we tested whether the contribution of FGF21 to liraglutide-induced weight loss is dependent on dietary carbohydrate content. In control and liver Fgf21 knockout (LivFgf21-/-) mice fed calorically matched diets with low- (LC) or high-carbohydrate (HC) content, we found that only HC-fed LivFgf21-/- mice were resistant to liraglutide-induced weight loss. Similarly, liraglutide-induced weight loss was partially impaired in LivFgf21-/- mice fed a high-fat, high-sugar (HFHS) diet. Lastly, we show that loss of neuronal {beta}-klotho expression also diminishes liraglutide-induced weight loss in mice fed a HC or HFHS diet, indicating that FGF21 mediates liraglutide-induced weight loss via neuronal FGF21 action. Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in the presence of high dietary carbohydrate content.

physiology↗

bioRxiv2021

OPA1 Deletion in Brown Adipose Tissue Improves Thermoregulation and Systemic Metabolism via FGF21

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including proteolytic processing of the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. By deleting OPA1 selectively in BAT (OPA1 BAT KO), we demonstrate that OPA1 is required for cold-induced thermogenesis. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)- dependent manner. BAT-derived FGF21 mediates an adaptive response in OPA1 BAT KO mice, by inducing browning of white adipose tissue (WAT), increasing resting metabolic rates, and improving thermoregulation. However, FGF21 does not mediate the resistance to diet-induced obesity observed in these animals. These findings reveal a requirement for OPA1 in BAT thermogenesis, and uncovers a homeostatic mechanism of BAT-mediated metabolic protection governed by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.

physiology↗

bioRxiv2020

ADH5-mediated NO Bioactivity Maintains Metabolic Homeostasis in Brown Adipose Tissue

Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status but the molecular mechanisms underlying this regulation are incompletely understood. Protein S-nitrosylation, the nitric oxide-mediated cysteine thiol modification of proteins, plays important roles in cellular redox regulation. Here we show that both diet-induced obesity (DIO) and acute cold exposure elevates protein S-nitrosylation of BAT proteins, including UCP1, to regulate thermogenesis. This effect in BAT is regulated largely by S-nitrosoglutathione reductase (GSNOR, ADH5), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 specifically in BAT impairs UCP1-dependent thermogenesis during acute cold challenge and worsens metabolic dysfunction during diet-induced obesity. Mechanistically, we demonstrate that Adh5 expression in BAT is controlled by the transcription factor heat shock factor 1 (HSF1) and administration of an HSF1 activator to the BAT of mice with DIO increased Adh5 expression and significantly improved UCP1-mediated mitochondrial respiration. Together, these data demonstrate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis which may be therapeutically targeted to improve metabolic health. HighlightsO_LIThermogenesis induces protein S-nitrosylation modification in the BAT; C_LIO_LIADH5, a major cellular denitrosylase, is required for maintaining BAT metabolic homeostasis under both overnutrition and cold stress conditions; C_LIO_LIDiet-induced obesity suppresses HSF1-mediated activation of Adh5 in the BAT; C_LIO_LIADH5 overexpression in BAT improves whole-body glucose homeostasis in obesity. C_LI

molecular biology↗

bioRxiv2019

NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress is associated with dysregulated metabolism, but little is known about how the ER responds to metabolic activity. Here, working primarily in mouse hepatocytes, we show that decreasing the availability of substrate for the TCA cycle diminished NADPH production and attenuated ER stress in a manner that depended on glutathione oxidation. ER stress was also alleviated by impairing either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity favored NADPH production, glutathione reduction, and ER stress. Validating these findings, we show that deletion of the mitochondrial pyruvate carrier, which is known to decrease TCA cycle activity and protect the liver from diet-induced injury, also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. These results provide independent genetic evidence that mitochondrial oxidative metabolism is linked to ER homeostasis. Our results demonstrate a novel pathway of communication between mitochondria and the ER, through relay of redox metabolites.

cell biology↗