Browsing by Subject "Energy expenditure"

Now showing 1 - 8 of 8
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    Chewing the Fat: A Metabolic Role for Ldb1 Beyond the Pancreas?
    (Endocrine Society, 2017-04-29) Sims, Emily K.; Pediatrics, School of Medicine
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    GCN2 is required to maintain core body temperature in mice during acute cold
    (American Physiological Society, 2023) Levy, Jordan L.; Mirek, Emily T.; Rodriguez, Esther M.; Zalma, Brian; Burns, Jeffrey; Jonsson, William O.; Sampath, Harini; Staschke, Kirk A.; Wek, Ronald C.; Anthony, Tracy G.; Biochemistry and Molecular Biology, School of Medicine
    Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis. In alignment with our hypothesis, female and male mice lacking GCN2 failed to adequately increase energy expenditure and veered into torpor. Mice administered a small molecule inhibitor of GCN2 were also profoundly intolerant to acute cold stress. Gcn2 deletion also impeded liver-derived FGF21 but in males only. Within the brown adipose tissue (BAT), acute cold exposure increased ISR activation and its transcriptional execution in males and females. RNA sequencing in BAT identified transcripts that encode actomyosin mechanics and transmembrane transport as requiring GCN2 during cold exposure. These transcripts included class II myosin heavy chain and amino acid transporters, critical for maximal thermogenesis during cold stress. Importantly, Gcn2 deletion corresponded with higher circulating amino acids and lower intracellular amino acids in the BAT during cold stress. In conclusion, we identify a sex-independent role for GCN2 activation to support adaptive thermogenesis via uptake of amino acids into brown adipose. NEW & NOTEWORTHY: This paper details the discovery that GCN2 activation is required in both male and female mice to maintain core body temperature during acute cold exposure. The results point to a novel role for GCN2 in supporting adaptive thermogenesis via amino acid transport and actomyosin mechanics in brown adipose tissue.
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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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    Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis
    (Frontiers Media, 2022-06-13) Wei, Lei; Shi, Jianjian; Pediatrics, School of Medicine
    Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.
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    ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice
    (Wiley, 2020-01) Wei, Lei; Surma, Michelle; Yang, Yang; Tersey, Sarah; Shi, Jianjian; Pediatrics, School of Medicine
    The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological and metabolic analyses in ROCK2+/− and ROCK2+/KD mouse models, the latter harboring an allele with a kinase-dead (KD) mutation. Both ROCK2+/− and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/− mice on a high-fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/− stromal-vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro-beige phenotype of ROCK2+/− SV cells. In conclusion, ROCK2 activity-mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age-related and diet-induced fat mass gain and insulin resistance.
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    The Role of Mediobasal Hypothalamic PACAP in the Control of Body Weight and Metabolism
    (Oxford University Press, 2021) Bozadjieva-Kramer, Nadejda; Ross, Rachel A.; Johnson, David Q.; Fenselau, Henning; Haggerty, David L.; Atwood, Brady; Lowell, Bradford; Flak, Jonathan N.; Pharmacology and Toxicology, School of Medicine
    Body energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus. This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAVCre) injections to ablate Adcyap1 (gene coding for PACAP) in mice (Adcyap1MBHKO mice). Adcyap1MBHKO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1MBHKO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis. While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1MBHKO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis.
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    tTARGIT AAVs mediate the sensitive and flexible manipulation of intersectional neuronal populations in mice
    (eLife Sciences, 2021-03-11) Sabatini, Paul V.; Wang, Jine; Rupp, Alan C.; Affinati, Alison H.; Flak, Jonathan N.; Li, Chien; Olson, David P.; Myers, Martin G.; Pharmacology and Toxicology, School of Medicine
    While Cre-dependent viral systems permit the manipulation of many neuron types, some cell populations cannot be targeted by a single DNA recombinase. Although the combined use of Flp and Cre recombinases can overcome this limitation, insufficient recombinase activity can reduce the efficacy of existing Cre+Flp-dependent viral systems. We developed a sensitive dual recombinase-activated viral approach: tTA-driven Recombinase-Guided Intersectional Targeting (tTARGIT) adeno-associated viruses (AAVs). tTARGIT AAVs utilize a Flp-dependent tetracycline transactivator (tTA) 'Driver' AAV and a tetracycline response element-driven, Cre-dependent 'Payload' AAV to express the transgene of interest. We employed this system in Slc17a6FlpO;LeprCre mice to manipulate LepRb neurons of the ventromedial hypothalamus (VMH; LepRbVMH neurons) while omitting neighboring LepRb populations. We defined the circuitry of LepRbVMH neurons and roles for these cells in the control of food intake and energy expenditure. Thus, the tTARGIT system mediates robust recombinase-sensitive transgene expression, permitting the precise manipulation of previously intractable neural populations.
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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.