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Principal Investigator: E DOUGLAS LEWANDOWSKI
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $769,850
Funding agency: National Heart Lung and Blood Institute
Project Summary:
The pathogenesis of heart failure is linked to systemic metabolic dysfunction, a comorbidity likely involving
peripheral organs, and resulting in insulin resistance in patients with and without diabetes. This study focuses
on the reciprocal response of adipose tissue to pathological stress on the heart and will investigate how
adipose tissue activity affects cardiac metabolic remodeling. This proposal originates from novel findings by
each of the MPI laboratories. We have identified transient changes in adipose tissue plasticity during the
pathogenesis of decompensated cardiac hypertrophy in response to pathological stress alone, absent any
primary metabolic stress, such as diabetes, nutrient overload, or obesity. This finding and our unpublished data
implicate cardiac natriuretic peptides (NP) as mediators of adipose activation and show that NPs are induced
by a reduction in long chain fatty acid (LCFA) oxidation by the heart, even without pathological stress.
Preliminary data reveal a profound, sex-specific array of early responses in white (WAT) and brown (BAT)
adipose tissue activity to cardiac pressure overload that include beiging of WAT and induction of a lipolytic
phenotype with cold exposure. While the cardiac responses to pathological stress include maladaptive
remodeling of lipid metabolism, the effects of adipose plasticity on the cardiac lipid profile during the
development of pathological hypertrophy are virtually unexplored. Thus, we hypothesize that: 1) the
metabolic response of reduced fatty acid oxidation in the heart during pathological stress induces plasticity of
WAT that is mediated by cardiac NPs in a sex-specific manner, distinct from β-adrenergic stimulation, with
downstream effects on glucose tolerance; and 2) sustained beiging of WAT and activation of BAT confer
cardioprotection against adverse cardiac metabolic remodeling. The research design supports three specific
aims: 1. Elucidate effects of adipocyte adrenergic activation on WAT beiging, and responses of cardiac LCFA
metabolism during TAC with adipose adrenergic activation and inhibition; 2. Determine whether adipose
plasticity results from NP effects in direct response to TAC or from the metabolic shift of reduced LCFA
oxidation in male and female mice; 3. Investigate a potential cardioprotective role of adipose browning on the
lipid profile of failing hearts. The overall objectives are to: 1) determine the reciprocal metabolic responses
between the pathologically stressed heart and adipose tissue via cardiac NP production and adipokine/lipokine
release (namely 12,13-diHOME), respectively; 2) elucidate the consequences of sex differences in the
responses of adipose tissue and myocardium to cardiac stress; and 3) explore the potential for WAT beiging or
BAT activation to provide cardioprotection via metabolic signaling. The findings will contribute new insights into
the adipose responses and contributions to metabolic remodeling of the heart during the pathogenesis of
decompensated cardiac hypertrophy, with the potential to identify targets for remediating the progression to
overt heart failure and improving peripheral and systemic metabolic dysfunction.
Terms: <Adipocytes><Adipose Cell><Adipose tissue><Adrenergic Agents><Adrenergic Drugs><Adrenergic Receptor><Adrenergics><Adrenoceptors><Affect><Agonist><Aortic Stenosis><Aortic Valve Stenosis><BAT uncoupling protein><Blood Vessels><Brown Adipose Tissue><Brown Fat><CPT 1><Cardiac><Carnitine Acyltransferase I><Carnitine O-Palmitoyltransferase><Carnitine Palmitoyltransferase><Carnitine Palmitoyltransferase I><Catecholamines><Cell Communication and Signaling><Cell Signaling><Characteristics><Common Rat Strains><Data><Development><Diabetes Mellitus><Differences between sexes><Differs between sexes><EFRAC><Ejection Fraction><Enzyme Gene><Enzymes><Epinephrine Receptors><Fat Cells><Fats><Fatty Acid Metabolism Pathway><Fatty Tissue><Fatty acid glycerol esters><Female><Genes><Heart><Heart Hypertrophy><Heart Muscle tissue><Heart failure><Heat Production><Hibernating Gland><Human><Hypertrophy><Hypothermia><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><Isoforms><Laboratories><Link><Lipids><Lipocytes><Lipolysis><Liver><Mature Lipocyte><Mature fat cell><Mediating><Mediator><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolic stress><Metabolism><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Murine><Mus><Myocardial tissue><Myocardium><Myosin Heavy Chains><Natriuretic Peptide Hormones><Natriuretic Peptides><Nutrient><Obesity><Organ><Outcome><Palmitoylcarnitine Transferase><Palmitylcarnitine Acyltransferase><Pathogenesis><Pathologic><Patients><Peripheral><Phase><Phenotype><Production><Protein Isoforms><Publishing><Rat><Rats Mammals><Rattus><Receptor Activation><Receptors, Adrenergic, beta-3><Research><Research Design><Role><Sex Differences><Sexual differences><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stress><Study Type><Sympathins><Testing><Thermogenesis><Tissue Transplantation><adenoreceptor><adipocytokines><adipokines><adipose><adiposity><antagonism><antagonist><aorta constriction><beta3 Adrenoreceptor><biological signal transduction><brown adipose tissue uncoupling protein><cardiac failure><cardiac hypertrophy><cardiac metabolism><cardiac muscle><cardioprotectant><cardioprotection><cardioprotective><carnitine palmitoyltransferase 1><co-morbid><co-morbidity><comorbidity><corpulence><developmental><diabetes><event cycle><fat metabolism><fatty acid metabolism><fatty acid oxidation><glucose tolerance><heart failure and reduced ejection fraction><heart failure with reduced ejection fraction><heart metabolism><heart muscle><hepatic body system><hepatic organ system><improved><insight><insulin resistant><insulin sensitivity><insulin tolerance><interest><knock-down><knockdown><lipid metabolism><long chain fatty acid><male><mitochondrial><mouse model><murine model><myosin heavy chain><natural hypothermia><novel><overexpress><overexpression><oxidation><preservation><pressure><remediation><response><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social role><stem><study design><subcutaneous><subdermal><thermogenin><uncoupling protein 1><uptake><vascular><virtual><white adipose tissue><yellow adipose tissue>