Obese individuals have more (hyperplastic) and larger (hypertrophic) adipocytes in their white adipose tissue (WAT) than normal-weight individuals. The difference in cell number emerges early in childhood, suggesting that this is a critical period for being susceptible to obesity. Breast-feeding has been shown to be protective against obesity, and we have previously shown in mice that the physical structure of lipids in human milk may contribute to this protective effect. In the present study, we investigated how differences in the physical structure of lipids in the early diet may modulate adipose tissue development. Male mice were fed a diet containing control infant milk formula (Control IMF; Danone Research) or Nuturis w (Concept IMF with large phospholipid-coated lipid droplets; Danone Research) from postnatal day (PN)16 to 42. Subsequently, mice were challenged with a moderate Western-style diet (WSD) until PN98, and body composition was monitored by dual-energy X-ray absorptiometry. Epididymal WAT was analysed for adipocyte size, number and gene expression of metabolic transcription factors. Early Concept IMF exposure reduced fat accumulation during the WSD challenge by 30 % compared with the Control IMF. It reduced adipocyte size without affecting adipocyte number in adult mice. The Concept IMF decreased the expression of PPARg, CCAAT/enhancer-binding protein and retinoid X receptor a in WAT in adulthood, key regulators of metabolic activity. In conclusion, Concept IMF exposure in early life reduced susceptibility to obesity in adult life, by preventing adipocyte hypertrophia upon adult dietary challenge without affecting adipogenesis. These data emphasise the importance of the physical properties of dietary lipids in early life in obesity risk later in life.

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In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPAR alpha-/- mice, indicating that PPAR alpha is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPAR alpha-dependent hepatic carnitine accumulation we measured carnitine biosynthesis enzyme activities, levels of carnitine biosynthesis intermediates, acyl-carnitines and OCTN2 mRNA levels in tissues of untreated, fasted or Wy-14643-treated wild type and PPAR alpha-/- mice. Here we show that both enhancement of carnitine biosynthesis (due to increased gamma-butyrobetaine dioxygenase activity), extra-hepatic gamma-butyrobetaine synthesis and increased hepatic carnitine import (OCTN2 expression) contributes to the increased hepatic carnitine levels after fasting and that these processes are PPAR alpha-dependent.

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.

Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is the most common long-chain fatty acid oxidation defect and presents with heterogeneous clinical manifestations. Accumulation of long-chain acylcarnitines and deficiency of free carnitine have often been proposed to play an important role in disease pathogenesis. The VLCAD-deficient mouse exhibits similar clinical and biochemical phenotypes to those observed in humans and, therefore, represents an excellent model to study VLCAD deficiency. We measured carnitine and acylcarnitine profiles in liver, skeletal muscle (SkM), bile, and blood from VLCAD knock-out mice and controls under nonstressed and various stress conditions. Carnitine and acylcarnitines were extracted from body fluids with methanol and from tissues with acetonitrile, respectively, and were analyzed as their butyl esters using electrospray ionization tandem mass spectrometry. Fasting combined with a cold challenge for 8 h significantly induced liver long-chain acylcarnitine and free carnitine production. Acylcarnitines in SkM predominantly accumulated during exercise with a concomitant decrease of free carnitine. Changes in blood free carnitine did not correlate with carnitine homeostasis in liver and SkM. Our results demonstrate different tissue-specific long-chain acylcarnitine profiles in response to various stressors, which may be of importance with respect to the heterogeneous clinical manifestations of VLCAD deficiency in humans. Furthermore, we conclude that carnitine biosynthesis in the liver seems sufficiently active to maintain liver carnitine levels during increased demand. Our data suggest that carnitine supplementation in long-chain ␤-oxidation defects may not be required, and blood carnitine concentrations do not reflect tissue carnitine homeostasis. Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is the most common mitochondrial ␤-oxidation defect of long-chain fatty acids, with an incidence of~1:50,000 to 1:100,000 births (1). In humans, three distinct clinical phenotypes of different severities occur: a life-threatening, early-onset presentation with cardiomyopathy and hepatopathy; a hepatic phenotype with recurrent hypoketotic hypoglycemia and onset in infancy; and a milder, myopathic form with episodic muscle weakness, myalgia, and rhabdomyolysis presenting in adolescence or adulthood (2). Treatment interventions such as avoidance of fasting, reduced long-chain fat intake, and supplementation with medium-chain triglycerides may avoid metabolic decompensation, and long-term rehabilitation can be achieved (3,4).Characteristically, long-chain acyl-CoAs accumulate in mitochondria. To leave the mitochondria, they are converted into acylcarnitine esters, which can be assayed in blood (5). As a result of an increased production of acylcarnitines, blood free carnitine concentrations may decrease (5), a condition termed secondary carnitine deficiency. Nevertheless, supplementation of exogenous carnitine to restore intracellular carnitine pools has been controversia...