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Although aging is associated with progressive adiposity and a decline in liver function, the underlying molecular mechanisms and metabolic interplay are incompletely understood. Here, we demonstrate that aging induces hepatic protein kinase Cbeta (PKCβ) expression, while hepatocyte PKCβ deficiency (PKCβ Hep-/- ) in mice significantly attenuates obesity in aged mice fed a high-fat diet. Compared with control PKCβ fl/fl mice, PKCβ Hep-/- mice showed elevated energy expenditure with augmentation of oxygen consumption and carbon dioxide production which was dependent on β3-adrenergic receptor signaling, thereby favoring negative energy balance. This effect was accompanied by induction of thermogenic genes in brown adipose tissue (BAT) and increased BAT respiratory capacity, as well as a shift to oxidative muscle fiber type with an improved mitochondrial function, thereby enhancing oxidative capacity of thermogenic tissues. Furthermore, in PKCβ Hep-/- mice, we determined that PKCβ overexpression in the liver mitigated elevated expression of thermogenic genes in BAT. In conclusion, our study thus establishes hepatocyte PKCβ induction as a critical component of pathophysiological energy metabolism by promoting progressive hepatic and extrahepatic metabolic derangements in energy homeostasis, contributing to late-onset obesity. These findings have potential implications for augmenting thermogenesis as a means of combating aging-induced obesity., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-β1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-β1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-β1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-β1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-β1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-β1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current (I Na,L ) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility., Methods: Here, we investigated a possible role for CaMKII-dependent I Na,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Na v 1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice)., Results: A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity., Conclusions: These data demonstrate a novel role for CaMKII-dependent regulation of Na v 1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

Background: Studies have demonstrated that exposure to fine particulate matter (PM 2.5 ) is linked to cardiovascular disease (CVD), which is exacerbated in patients with pre-existing conditions such as obesity. In the present study, we examined cardiac function of obese mice exposed to PM 2.5 and determined if mild exercise affected cardiac function., Methods: Obese mice (ob/ob) (leptin deficient, C57BL/6J background) were exposed to either filtered air (FA) or PM 2.5 at an average concentration of 32 μg/m 3 for 6 h/day, 5 days/week for 9 months. Following exposure, mice were divided into four groups: (1) FA sedentary, (2) FA treadmill exercise, (3) PM 2.5 sedentary, and (4) PM 2.5 treadmill exercise and all mice were analyzed after 8 weeks of exercise training., Results: Echocardiography showed increased left ventricular end systolic (LVESd) and diastolic (LVEDd) diameters in PM 2.5 sedentary mice compared to FA sedentary mice. There was increased expression of ICAM1, VCAM and CRP markers in sedentary PM 2.5 mice compared to FA mice. Both FA and PM 2.5 exercised mice showed decreased posterior wall thickness in systole compared to FA sedentary mice, coupled with altered expression of inflammatory markers following exercise., Conclusion: Obese mice exposed to PM 2.5 for 9 months showed cardiac dysfunction, which was not improved following mild exercise training., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.