Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60-90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M mice. Lysine acetylation was reduced by ∼50% in Cpt2M hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth.

SDS with digestion into the ileum reduced daily food intake and paralleled suppressed expression of appetite-stimulating neuropeptide genes associated with the gut-brain axis. This novel finding suggests further exploration involving a clinical study and potential development of SDS-based functional foods as an approach to obesity control.

Glycemic carbohydrates in foods are an important macronutrient providing the biological fuel of glucose for a variety of physiological processes. A classification of glycemic carbohydrates into rapidly digestible carbohydrate (RDC) and slowly digestible carbohydrate (SDC) has been used to specify their nutritional quality related to glucose homeostasis that is essential to normal functioning of the brain and critical to life. Although there have been many studies and reviews on slowly digestible starch (SDS) and SDC, the mechanisms of their slow digestion and absorption were mostly investigated from the material side without considering the physiological processes of their in vivo digestion, absorption, and most importantly interactions with other food components and the gastrointestinal tract. In this article, the physiological processes modulating the bioavailability of carbohydrates, specifically the rate and extent of their digestion and absorption as well as the related locations, in a whole food context, will be discussed by focusing on the activities of the gastrointestinal tract including glycolytic enzymes and glucose release, sugar sensing, gut hormones, and neurohormonal negative feedback mechanisms. It is hoped that a deep understanding of these physiological processes will facilitate the development of innovative dietary approaches to achieve desired carbohydrate or glucose bioavailability for improved health.

We sought to determine whether design of carbohydrate-based microspheres to have different digestion rates, while retaining the same material properties, could modulate gastric emptying through the ileal brake. Microspheres made to have three slow digestion rates and a rapidly digested starch analog (maltodextrin) were administrated to rats by gavage and starch contents in the stomach, proximal and distal small intestine, and cecum were measured 2 h post-gavage. A stepwise increase in the amount of starch retained in the stomach was found for microspheres with incrementally slower rates of digestion. Postprandial glycaemic and insulinemic responses were incrementally lower for the different microspheres than for the rapidly digestible control. A second-meal effect was observed for slowly digestible starch microspheres compared to glucose. Thus, dietary slowly digestible carbohydrates were designed to elicit incremental significant changes in gastric emptying, glycaemic and insulinemic responses, and they may be a means to trigger the ileal brake.

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Carnitine palmitoyltransferase 2 (CPT2) is an enzyme required for the acyl‐carnitine shuttle that controls mitochondrial long‐chain fatty acid oxidation. The role of CPT2 in fatty acid metabolism is well established. However, patients with early‐onset CPT2 deficiency suffer cardiac complications and it has remained unknown how the loss of CPT2 in the heart alters cardiac function due to the lack of a physiological model. Here we present a novel mouse model deficient in cardiac CPT2 (Cpt2M−/−) which causes severe cardiac hypertrophy and eventual cardiac failure. Cpt2M−/− hearts weigh up to 4‐fold that of control hearts within 8–12 weeks of age and the mice fail to survive beyond 15 weeks of age. The Cpt2M−/− mice maintain a normal body weight and adiposity during their short lifespan. The loss of cardiac CPT2 reduced long‐chain fatty acid oxidation in heart homogenates by 93%. The loss of cardiac CPT2 increases the abundance of mitochondrial proteins, protein acetylation, activation of the mTOR pathway, and reduces insulin‐stimulated induction of the insulin‐signaling pathway. Together, these data suggest that CPT2‐mediated flux of fatty acid oxidation is required to retain insulin sensitivity and to sustain cardiac function.