Objective: To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short-term overfeeding in healthy subjects. Design and methods: The analysis of the data collected in several studies in which fasting hepatic glucose production (HGP), hepatic insulin sensitivity index (HISI), and intrahepatocellular lipids (IHCL) had been measured after both 6-7 days on a weight-maintenance diet (control, C; n ¼ 55) and 6-7 days of overfeeding with 1.5 (F1.5, n ¼ 7), 3 (F3, n ¼ 17), or 4 g fructose/kg/day (F4, n ¼ 10), with 3 g glucose/ kg/day (G3, n ¼ 11), or with 30% excess energy as saturated fat (fat30%, n ¼ 10). Results: F3, F4, G3, and fat30% all significantly increased IHCL, respectively by 113 6 86, 102 6 115, 59 6 92, and 90 6 74% as compared to C (all P < 0.05). F4 and G3 increased HGP by 16 6 10 and 8 6 11% (both P < 0.05), and F3 and F4 significantly decreased HISI by 20 6 22 and 19 6 14% (both P < 0.01). In contrast, there was no significant effect of fat30% on HGP or HISI. Conclusions: Short-term overfeeding with fructose or glucose decreases hepatic insulin sensitivity and increases hepatic fat content. This indicates short-term regulation of hepatic glucose metabolism by simple carbohydrates.

Object Deep brain stimulation (DBS) of the lateral hypothalamic area (LHA) has been suggested as a potential treatment for intractable obesity. The authors present the 2-year safety results as well as early efficacy and metabolic effects in 3 patients undergoing bilateral LHA DBS in the first study of this approach in humans. Methods Three patients meeting strict criteria for intractable obesity, including failed bariatric surgery, under-went bilateral implantation of LHA DBS electrodes as part of an institutional review board– and FDA-approved pilot study. The primary focus of the study was safety; however, the authors also received approval to collect data on early efficacy including weight change and energy metabolism. Results No serious adverse effects, including detrimental psychological consequences, were observed with continuous LHA DBS after a mean follow-up of 35 months (range 30–39 months). Three-dimensional nonlinear transformation of postoperative imaging superimposed onto brain atlas anatomy was used to confirm and study DBS contact proximity to the LHA. No significant weight loss trends were seen when DBS was programmed using standard settings derived from movement disorder DBS surgery. However, promising weight loss trends have been observed when monopolar DBS stimulation has been applied via specific contacts found to increase the resting metabolic rate measured in a respiratory chamber. Conclusions Deep brain stimulation of the LHA may be applied safely to humans with intractable obesity. Early evidence for some weight loss under metabolically optimized settings provides the first “proof of principle” for this novel antiobesity strategy. A larger follow-up study focused on efficacy along with a more rigorous metabolic analysis is planned to further explore the benefits and therapeutic mechanism behind this investigational therapy.

Fructose increased total carbohydrate oxidation, lactate production and oxidation, and GNG(F). Fructose oxidation was explained equally by fructose-derived lactate and glucose oxidation, most likely in skeletal and cardiac muscle. This trial was registered at clinicaltrials.gov as NCT01128647.

Excess fructose intake causes hypertriglyceridemia and hepatic insulin resistance in sedentary humans. Since exercise improves insulin sensitivity in insulin-resistant patients, we hypothesized that it would also prevent fructose-induced hypertriglyceridemia. This study was therefore designed to evaluate the effects of exercise on circulating lipids in healthy subjects fed a weight-maintenance, high-fructose diet. Eight healthy males were studied on three occasions after 4 days of 1) a diet low in fructose and no exercise (C), 2) a diet with 30% fructose and no exercise (HFr), or 3) a diet with 30% fructose and moderate aerobic exercise (HFrEx). On all three occasions, a 9-h oral [13C]-labeled fructose loading test was performed on the fifth day to measure [13C]palmitate in triglyceride-rich lipoprotein (TRL)-triglycerides (TG). Compared with C, HFr significantly increased fasting glucose, total TG, TRL-TG concentrations, and apolipoprotein (apo)B48 concentrations as well as postfructose glucose, total TG, TRL-TG, and [13C]palmitate in TRL-TG. HFrEx completely normalized fasting and postfructose TG, TRL-TG, and [13C]palmitate concentration in TRL-TG and apoB48 concentrations. In addition, it increased lipid oxidation and plasma nonesterified fatty acid concentrations compared with HFr. These data indicate that exercise prevents the dyslipidemia induced by high fructose intake independently of energy balance.

The increase in VLDL TAG concentration after ingestion of a high-fructose diet is more pronounced in men than in pre-menopausal women. We hypothesised that this may be due to a lower fructose-induced stimulation of de novo lipogenesis (DNL) in pre-menopausal women. To evaluate this hypothesis, nine healthy male and nine healthy female subjects were studied after ingestion of oral loads of fructose enriched with 13 C 6 fructose. Incorporation of 13 C into breath CO 2 , plasma glucose and plasma VLDL palmitate was monitored to evaluate total fructose oxidation, gluconeogenesis and hepatic DNL, respectively. Substrate oxidation was assessed by indirect calorimetry. After 13 C fructose ingestion, 44·0 (SD 3·2) % of labelled carbons were recovered in plasma glucose in males v. 41·9 (SD 2·3) % in females (NS), and 42·9 (SD 3·7) % of labelled carbons were recovered in breath CO 2 in males v. 43·0 (SD 4·5) % in females (NS), indicating similar gluconeogenesis from fructose and total fructose oxidation in males and females. The area under the curve for 13 C VLDL palmitate tracer-to-tracee ratio was four times lower in females (P,0·05), indicating a lower DNL. Furthermore, lipid oxidation was significantly suppressed in males (by 16·4 (SD 5·2), P, 0·05), but it was not suppressed in females (2 1·3 (SD 4·7) %). These results support the hypothesis that females may be protected against fructose-induced hypertriglyceridaemia because of a lower stimulation of DNL and a lower suppression of lipid oxidation. De novo lipogenesis: VLDL TAG: Endogenous glucose productionThe metabolic effects of a high-fructose diet have been widely studied in both animals and human subjects (1) . High-fructose diet is associated with the development of at least two features of the metabolic syndrome, i.e. insulin resistance and increased plasma VLDL TAG. The latter may in turn be associated with an increased production of small, dense LDL particle with high atherogenic potential (2,3) . It has been reported by several authors that a high-fructose diet increases plasma TAG less and does not reduce insulin sensitivity in both pre-menopausal women and female rodents compared with males (4 -11) . This may be due to a sex-specific difference in either fructose metabolism or adaptations to chronic fructose overfeeding. To our knowledge, whether the metabolism of an acute fructose load differs in females and males has not been specifically assessed. Fructose disposal relies mainly on the stimulation of carbohydrate oxidation (fructose oxidation in splanchnic organs and indirect oxidation of glucose and lactate synthesised from the fructose), gluconeogenesis, hepatic glycogen storage and hepatic de novo lipogenesis (DNL). The latter, although a quantitatively minor pathway for fructose disposal, may be closely linked to hepatic VLDL TAG production and synthesis of intra-hepatic lipids. Therefore, we hypothesised that fructose-induced stimulation of DNL may be blunted in pre-menopausal women.To evaluate this hypothesis, we compared the metabolic fate of i...

Our results confirm an important role for leptin as an independent determinant of the metabolic adaptation in response to CR.

O besity is a significant health challenge, with the latest projections estimating that there will be 2.16 billion overweight and 1.12 billion obese individuals globally by 2030. In addition to social stigmatization and impaired quality of life, obese people are faced with significantly increased risk of cardiovascular disease, type 2 diabetes mellitus, and a number of cancers. Weight gain results from a sustained imbalance between energy intake (calories consumed) and energy expenditure (calories burned), resulting in positive energy balance. To tip energy balance toward weight loss, not only should food intake be decreased, but increasing physical activity may help. It is important to realize, however, that the secular rises in obesity over the past 3 to 4 decades can be explained by both physiological and environmental drivers and a number of putative factors ( Figure 1). 1,2 At one level, the obesity epidemic is a classic gene-environment interaction in which the human genotype is susceptible to environmental influences that affect energy intake and expenditure, with the obesogenic environment being dominant. These environmental factors include the 2 obvious explanations, ie, reduced physical activity and increased energy intake from high-calorie food and drinks, with the latter likely being the dominant factor. 3 However, other less studied factors have been implicated, including longer time spent awake, increased mean age of mothers at first birth, decreased prevalence of smoking, presence of environmental pollutants, ingestion of many novel medications, and reduction in the variability of seasonal ambient temperature owing to the presence of almost ubiquitous air conditioning. 4 Fundamentally, the obesity epidemic is explained by a dysregulation of energy balance in our obesogenic environment. Understanding the cause of obesity requires the study of how genetic and environmental factors interact to produce long-term positive energy balance.As a consequence of the obesogenic environment, the treatment of obesity requires intensive lifestyle modification. However, lifestyle modification in obese individuals tends to provide only transient success, and pharmacological treatment of obesity has often been disappointing and is very contentious because of the many safety concerns. Other approaches such as bariatric surgery are costly and not without risk. Thus, there is a concerted effort to find novel strategies to reduce excess body weight. This includes the potential of increasing energy expenditure via the stimulation of brown adipose tissue (BAT), now known to be present in adult humans. We would expect that such physiological or pharmacological stimulation of thermogenesis (heat production) would lead to dissipation of at least some excess ingested calories. This review provides a historical overview on the research on BAT, highlights recent developments in the field, and concludes with a discussion of the relevant issues that need to be addressed before BAT is considered a therapeutic option for human obe...

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