Metabolic role of the hepatic valine/3-hydroxyisobutyrate (3-HIB) pathway in fatty liver disease

Background: The valine (branched-chain amino acid) metabolite 3-hydroxyisobutyrate (3-HIB), produced by 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), is associated with insulin resistance and type 2 diabetes, but implicated tissues and cellular mechanisms are poorly understood. We hypothesized that HIBCH and 3-HIB regulate hepatic lipid accumulation. Methods: HIBCH mRNA in human liver biopsies (“Liver cohort”) and plasma 3-HIB (“CARBFUNC” cohort) were correlated with fatty liver and metabolic markers. Human Huh7 hepatocytes were supplemented with fatty acids (FAs) to induce lipid accumulation. Following HIBCH overexpression, siRNA knockdown, inhibition of PDK4 (a marker of FA β-oxidation) or 3-HIB supplementation, we performed RNA-seq, Western blotting, targeted metabolite analyses and functional assays. Findings: We identify a regulatory feedback loop between the valine/3-HIB pathway and PDK4 that shapes hepatic FA metabolism and metabolic health and responds to 3-HIB treatment of hepatocytes. HIBCH overexpression increased 3-HIB release and FA uptake, while knockdown increased cellular respiration and decreased reactive oxygen species (ROS) associated with metabolic shifts via PDK4 upregulation. Treatment with PDK4 inhibitor lowered 3-HIB release and increased FA uptake, while increasing HIBCH mRNA. Implicating this regulatory loop in fatty liver, human cohorts show positive correlations of liver fat with hepatic HIBCH and PDK4 expression (Liver cohort) and plasma 3-HIB (CARBFUNC cohort). Hepatocyte 3-HIB supplementation lowered HIBCH expression and FA uptake and increased cellular respiration and ROS. Interpretation: These data implicate the hepatic valine/3-HIB pathway in mechanisms of fatty liver, reflected in increased plasma 3-HIB concentrations, and present possible targets for therapeutic intervention.publishedVersio

Diets differing in carbohydrate cellularity and amount similarly reduced visceral fat in people with obesity - a randomized controlled trial (CARBFUNC)

publishedVersio

(Re)Organising for Interaction within Innovation Networks: An Exploratory Study in the Public Sector

Issues around innovation have seen considerable increase of academic and managerial interest over the last decades. In parallel, the role of business relationships and networks has also attracted growing attention. Consequently, the concept of innovation networks (INs) is positioned at the interface of these two streams. At the core of the concept of INs is the proposition that relationships, i.e. interactions with other business partners, are critical for key innovation activities. However, research on INs has focused mostly on network structure-related aspects, while not providing enough insights into the processes of organising for interactions. In particular, this study explores the role of actors’ perceptions and interpretations regarding business relationships on how actors organise for innovation activities. Furthermore, this paper sheds light on the reciprocal influence that exists between cognition and action in such contexts, something that has been discussed in the field of organisational and cognitive science but not within innovation networks setting as part of business marketing studies. Longitudinal exploratory case study research was conducted, which analyses two ser- vice innovation processes in an innovation network in a district within a municipality of a North European country. Our study shows how INs evolve over time as actors shape (and reshape) the network through specific interactions within and between realms of the IN, whereby the diverse views held by different actors are confronted. In particular, we find that perceptions and interpretations of power distribution and strength of relationships emerge as relevant aspects to determine actors’ intentions toward organising both in the innovation development and the implementation phases. At the same time, the changes (such as initiation, development, and termination) in the relationships with other actors, actor groups, or realms of the IN affect the actors’ interpretations, thereby generat- ing a recursive interpretative path through which the innovation network is shaped

(Re)Organising for Interaction within Innovation Networks – An Exploratory Study in the Public Sector

Issues around innovation have seen considerable increase of academic and managerial interest over the last decades. In parallel, the role of business relationships and networks has also attracted growing attention. Consequently, the concept of innovation networks (INs) is positioned at the interface of these two streams. At the core of the concept of INs is the proposition that relationships, i.e. interactions with other business partners, are critical for key innovation activities. However, research on INs has focused mostly on network structure-related aspects, while not providing enough insights into the processes of organising for interactions. In particular, this study explores the role of actors’ perceptions and interpretations regarding business relationships on how actors organise for innovation activities. Furthermore, this paper sheds light on the reciprocal influence that exists between cognition and action in such contexts, something that has been discussed in the field of organisational and cognitive science but not within innovation networks setting as part of business marketing studies. Longitudinal exploratory case study research was conducted, which analyses two ser- vice innovation processes in an innovation network in a district within a municipality of a North European country. Our study shows how INs evolve over time as actors shape (and reshape) the network through specific interactions within and between realms of the IN, whereby the diverse views held by different actors are confronted. In particular, we find that perceptions and interpretations of power distribution and strength of relationships emerge as relevant aspects to determine actors’ intentions toward organising both in the innovation development and the implementation phases. At the same time, the changes (such as initiation, development, and termination) in the relationships with other actors, actor groups, or realms of the IN affect the actors’ interpretations, thereby generat- ing a recursive interpretative path through which the innovation network is shaped

Diets differing in carbohydrate cellularity and amount similarly reduced visceral fat in people with obesity - a randomized controlled trial (CARBFUNC)

Background & aims Visceral adipose tissue (VAT) volume is associated with common lifestyle diseases. Dietary quality, including food matrix and degree of carbohydrate cellularity, as well as the carbohydrate/fat ratio, may influence VAT volume. We aimed to determine the effects of isocaloric diets differing in either “cellularity”, a novel marker of dietary carbohydrate quality, or carbohydrate amount on visceral fat volume and anthropometric measures in adults with obesity. Methods In a randomized controlled trial of 193 people with obesity/central adiposity, we compared changes in VAT volume after 6 and 12 months, measured by abdominal computed tomography, on three isocaloric eating patterns based on “acellular” carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), “cellular” carbohydrate sources (minimally processed foods with intact cellular structures such as fruits, potatoes/tubers, and rice), or low-carbohydrate high-fat (LCHF) principles. Outcomes were compared by an intention-to-treat (ITT) analysis using constrained linear mixed-effects modelling (cLMM) providing baseline-adjusted change scores and proper missing data handling without imputation. Results 78 and 57 participants completed 6 and 12 months, respectively, with similar intakes of energy (females: 1820−2060 kcal, males: 2480−2550 kcal) and protein (16–17 energy percent, E%) throughout the intervention, and only modest reductions in energy from baseline. Reported dietary intakes were 42–44, 41–42, and 11–15 E% carbohydrate and 36–38, 37–38, and 66–70 E% fat in the acellular, cellular and LCHF groups, respectively. There were no significant between-group differences in VAT volume after 6 months (cellular vs. acellular [95% CI]: −55 cm³ [−545, 436]; LCHF vs. acellular [95% CI]: −225 cm³ [−703, 253]) or after 12 months (cellular vs. acellular [95% CI]: −122 cm³ [−757, 514]; LCHF vs. acellular [95% CI]: −317 cm³ [−943, 309]). VAT volume decreased significantly within all groups by 14–18% and 12–17% after 6 and 12 months, respectively. Waist circumference was reduced to a significantly greater degree in the LCHF vs. acellular group at 6 months (LCHF vs. acellular [95% CI]: −2.78 cm [−5.54, −0.017]). Conclusions Despite modest energy restriction, the three isocaloric eating patterns, differing in carbohydrate cellularity and amount, decreased visceral fat volume significantly and to a similar clinically relevant degree