Soon after birth, the human body is colonised by bacteria. Trillions of bacteria take up residence in the gut and perform a range of useful functions such as helping with digestion and absorption of nutrients, producing vitamins, preventing growth of pathogenic bacteria, and developing the immune system. In 2006, it was shown that the proportion of Bacteroidetes relative to Firmicutes was reduced in the guts of obese people compared with lean individuals and also in the guts of genetically obese mice compared with lean littermates. Researchers at Emory University have now shown that mice engineered to lack toll-like receptor 5 (TLR5) – a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection – are 20% heavier than normal mice and have elevated triglycerides, cholesterol and blood pressure as well as slightly elevated blood sugar and a decreased response to insulin. TLR5-deficient mice consume about 10% more food than wild type mice and, although they lose weight when food is restricted, they still show insulin resistance. On a high fat diet, TLR5-deficient mice gain more weight than normal mice and develop full-blown diabetes and fatty liver disease, mimicking “metabolic syndrome” which increases the risk of developing heart disease and diabetes in humans.

Treating TLR5-deficient mice with antibiotics to kill most of the bacteria in the intestine reduced their metabolic abnormalities and, conversely, transfer of intestinal bacteria from TLR5-deficient mice to germ-free wild type mice transferred many of the characteristics of metabolic syndrome, including increased appetite, obesity, elevated blood sugar, and insulin resistance. Although earlier studies had shown that greater numbers of Firmicutes bacteria lead to more calories being extracted from the diet, the TLR5-deficient mice had normal proportions of Firmicutes and Bacteroidetes but differed in the composition of bacterial species in the two families. The new study shows that, as well as influencing how well energy is absorbed from food, gut flora can also influence appetite and may contribute to human obesity and metabolic disease.

The study is published in Science Express.

Fatty acids can be stored as triacylglycerol in lipid droplets, typically within adipose tissue, and then later released by the action of triacylglycerol hydrolase (TGH, also known as carboxylesterase-3, Ces3). Under normal circumstances, the released fatty acids provide an energy source, but excessive accumulation of triacylglycerol in peripheral tissues is associated with obesity and is a risk factor for type II diabetes and cardiovascular disease.

Researchers at the University of Alberta, Canada, reasoned that blocking the action of TGH would lead to better blood lipid profiles, but might also result in accumulation of triacylglycerol in the liver. However, they have found that mice lacking TGH (tgh^-/-) display global metabolic benefits with no obvious down-side. In both fasted- and fed-states, the animals had reduced plasma triacylglycerol, apolipoprotein B, and fatty acid levels. Despite the attenuation of very low-density lipoprotein (VLDL) secretion, TGH deficiency did not increase hepatic triacylglycerol levels. The tgh^-/- mice exhibited increased food intake and energy expenditure without change in body weight, and these metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance.

The authors of the study, published in Cell Metabolism, suggest that pharmacological inhibition of TGH could be a useful therapeutic target, although cautioning that further work is required. It may be desirable to target TGH in specific tissues (e.g. hepatic versus adipose) but those subtleties have yet to be established.

Energy-conserving mechanisms that evolved as protective measures in an environment of restricted food supply and high demand for physical activity promote obesity in times of abundant food and low physical activity. ATP-sensitive potassium (K_ATP) channels in heart and skeletal muscle act as safety valves that limit action potentials to prevent energy depletion and are essential for survival and stress adaptation, but researchers at the Mayo Clinic, the University of Iowa, New York University School of Medicine and the University of Connecticut have now found that the channels also regulate cellular energy use under non-stressed physiological conditions and contribute to fat deposition and obesity.

Both when the animals were at rest or normally active, heart and skeletal muscles of mice lacking the K_ATP channel dissipated more energy as heat than those of wild type mice and the animals were resistant to increases in body weight caused by a Western-style high fat diet. However, since the animals’ muscles are also less efficient when exercising, they show lower endurance and are less capable of maintaining physical performance than wild type animals.

The authors hope that therapies that reduce the activity of K_ATP channels in a tissue-specific manner may have the potential to reduce obesity by making muscles more thermogenic at rest and less fuel efficient during exercise.

The study is published in the journal Cell Metabolism.

Activation of the NAD⁺-dependent deacetylase, sirtuin-1 (Sirt1), has been linked to increased longevity in various species although further studies are needed to establish its role in human ageing. The beneficial effects of calorie restriction on lifespan and the proposed anti-ageing properties of resveratrol have both been linked to activation of sirtuins, although not without controversy. In a significant departure from previous studies which have focussed on activating Sirt1, research carried out at Brown University and Rhode Island Hospital has now suggested that inhibiting Sirt1 may be a way to control obesity.

In the first in-depth study of the metabolic role of Sirt1 in the brain, the researchers found that inhibiting Sirt1 appears to help control food intake. Calorie restriction increases expression of Sirt1 specifically in the hypothalamus, the primary brain centre that regulates food intake and body weight so the team hypothesised that hypothalamic Sirt1 is a metabolic factor controlling food intake. ICV administration of the selective Sirt1 inhibitor, EX527, in fasted rats resulted in decreased food intake and body weight gain. The weight gain was less than that of pair-fed counterparts suggesting that the decrease in weight gain was not exclusively due to the reduced food intake. The effects were shown to be Sirt1-specific since both were reversed by co-administration of a Sirt1 activator at a dose which alone did not change either food intake or weight gain. Knock-down of Sirt1 expression by infusion of Sirt1 specific siRNAs directly into the arcuate nucleus of the hypothalamus also led to lower food consumption and smaller weight gain. Co-administration of the melanocortin antagonist, SHU9119, with EX527 completely attenuated the lower food intake and reduced weight gain caused by EX527, indicating a role for melanocortin signalling in mediating the effects of Sirt1 on energy balance. Inhibition of hypothalamic Sirt1 activity was also shown to reverse fasting-induced decreases in S6 kinase signalling and to increase levels of serum thyroid hormones, which are strong stimulators of basic metabolic rate and thermogenesis.

The authors propose that central Sirt1 senses the nutritional status of the body and regulates hypothalamic melanocortin signalling together with the S6K pathway to govern food intake and body weight, and suggest that agents targeting this pathway may show promise for the treatment of obesity and associated metabolic disorders.

The study is published in PLoSone.

‘Breakfast like a king, lunch like a prince, sup like a pauper’ is an old and well known proverb but a recently published study gives new insights into why following this advice might help to fight obesity and diabetes.

Researchers at ETH have suggested that eating snacks – even healthy ones – between meals leads to a vicious circle of physical inactivity and overeating, and could ultimately lead to diabetes. The team have identified a novel mechanism by which insulin regulates both metabolic and behavioural responses to food intake. Insulin produced by the pancreas as a result of feeding inhibits the forkhead box transcription factor, Foxa2. Foxa2 regulates fat metabolism in the liver but also influences neurons in the lateral hypothalamic area of the brain which is considered to be the classic ‘feeding centre’, controlling feeding, diurnal rhythm, sleep and sexual behaviour. In the fasted state, Foxa2 is active and promotes synthesis of melanin-concentrating hormone (MCH) and orexin, proteins with roles in controlling food intake and motivated behaviour. In obese mice, Foxa2 was found to be non-functional, regardless of whether the animals were fasted or fed. Genetically modified mice with permanently active Fox2a in their brains have more MCH and orexin, eat more and have increased insulin sensitivity. The levels of physical activity after feeding are also significantly higher, and more closely resemble those of fasted animals. Conditional activation of Foxa2 in the brains of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass.

The authors suggest that periods of fasting are important to ensure correct body weight since each time food is consumed, Fox2a is suppressed which reduces the motivation for physical activity and, consequently, energy expenditure. Prevention of Foxa2 phosphorylation may lead to increased levels of physical activity and could be a potential pharmacological target for the treatment of obesity and diabetes.

The study is published in the journal Nature.

The fibres that make up skeletal muscle broadly fall into two groups: Type I, ‘slow-twitch’ myofibres, and Type II, ‘fast-twitch’ myofibres. Slow-twitch fibres utilise oxidative metabolism for energy generation and are associated with endurance, whilst fast-twitch fibres use a mixture of oxidative and anaerobic metabolism but are quicker to fatigue. Sprinters have up to 80 per cent type II fibres while marathon runners have up to 90 per cent type I fibres. Those that have a more sedentary lifestyle have about the same percentage of both.

Obese individuals have relatively fewer Type I fibres compared to average-weight counterparts and Type I fibres are believed to confer resistance to obesity. Consistent with this, the numbers of Type I fibres decrease in response to inactivity and or a high-fat diet (HFD). Conversely, numbers of Type I fibres increase in response to exercise.

Researchers at Yale University School of Medicine have now identified MAPK phosphatase-1 (MKP-1) as a key player in the Type I/Type II shift in response to HFD. The group had previously shown that mice deficient in MKP-1 displayed increased energy expenditure and were resistant to diet-induced obesity. This new study, published in the Journal of Clinical Investigation, found that MKP-1 was overexpressed in skeletal muscle of mice in response to excess dietary fat.

MKP-1 dephosphorylates, and consequently deactivates, MAP kinases in the nucleus. In the study, MKP-1 overexpression reduced p38 MAPK-mediated phosphorylation of PPARγ coactivator 1α (PGC-1α), which plays a central role in maintaining levels of Type I myofibres. The phosphorylation of PGC-1α is believed to stabilise the protein and, consistent with this, MKP-1 deficient mice had higher levels of PGC-1α in skeletal muscle than did wild-type mice and were refractory to the loss of Type I myofibres when fed a high-fat diet.

The incretin, glucagon-like peptide-1 (GLP-1), is an intestinal hormone that stimulates production and release of insulin from pancreatic beta cells. Consequently there has been considerable interest in mimicking the activity of GLP-1 for treatment of metabolic disorders such as Type-II diabetes and obesity. There are currently two approved classes of drug that modulate GLP-1 activity: analogues of GLP-1 and inhibitors of dipeptidyl peptidase IV (DPPIV). Analogues of GLP-1, such as the 39-residue synthetic peptide, exenatide, activate the GLP-1 receptor but are resistant to proteolytic cleavage by DPPIV. The gliptins, such as sitagliptin, inhibit DPPIV, extending the half-life of the natural hormone.

Researchers at Ecole Polytechnique Fédérale de Lausanne, in collaboration with the University of Perugia and Intercept Pharmaceuticals, have now published data showing that stimulation of TGR5, a G-protein coupled receptor, leads to release of GLP-1 in obese mice. The same group had previously demonstrated that activation of TGR5 in brown adipose tissue and muscle by endogenous bile acids boosted energy expenditure and reversed diet-induced obesity in mice.

In the current work the researchers used a combination of genetic gain- and loss-of-function studies together with the TGR5 agonist, INT-777, to show the link between TGR5 signalling and GLP-1 secretion. In vitro experiments with INT-777 in enteroendocrine L-cells confirmed the induction of GLP-1 secretion and that this was linked to increased intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization.

The study, published in the September 2^nd edition of Cell Metabolism, opens up a potential third route to modulation of GLP-1 activity and treatment of metabolic disorders.

The nuclear receptor, PPARγ, has hitherto been regarded as the master regulator of adipogenesis, without which new adipose tissue cannot be formed. Adipogenesis plays a key role in obesity and associated metabolic diseases such as type II diabetes and the thiazolidines, which target PPARγ are widely used to treat type II diabetes. Researchers at the University of Central Florida have now discovered, however, that monocyte chemotactic protein-1 (MCP-1)-induced protein (MCPIP), can trigger adipogenesis without involvement of PPARγ. The authors had previously shown that binding of MCP-1 to its receptor, CCR2, leads to induction of the Zn-finger protein, MCPIP. In the present study, MCP-1 was found to be produced, and MCPIP to be induced, before induction of PPARγ or other transcription factors in fibroblasts undergoing differentiation into adipocytes. Knockdown of MCPIP using siRNA was found to inhibit both gene induction and adipogenesis whereas treatment with MCP-1 or forced expression of MCPIP induced adipogenesis. Forced expression of MCPIP was also shown to induce adipogenesis in PPARγ-/- mouse embryonic fibroblasts, further demonstrating that MCPIP can act independently of PPARγ.

Obesity is well known to increase MCP-1 levels and the finding that MCPIP is able to induce adipogenesis without involvement of PPARγ provides new mechanistic evidence for the role of MCP-1/CCR2 in obesity and type II diabetes. Since there is experimental evidence that MCPIP promotes angiogenesis, MCP-1/CCR2 interaction could promote the formation of new blood vessels to supply blood to growing adipose tissue as well as promoting development of the adipocytes. A drug that could block the function of MCPIP may thus have the potential to treat obesity and type II diabetes.

The study is published in the online edition of Journal of Biological Chemistry.

Vinegar can be made from almost any carbohydrate source – the action of yeast first ferments the natural sugars to alcohol which is then converted into acetic acid by acetic acid bacteria. Vinegars typically contain around 5% acetic acid together with a variety of other components including polyphenols and organic acids.

Vinegars have been used for thousands of years as food preservatives and flavourings and, over the years, have also acquired a reputation for many health benefits. The human evidence for many of these claims remains equivocal although several studies have confirmed the anti-glycaemic properties of vinegar.

Largely anecdotal evidence has pointed to positive effects on weight loss and at a recent meeting of the Japan Society of Nutrition and Food Science, scientists at the Mizkan Central Research Institute have now described reductions in waist size, abdominal fat and blood neutral fat in overweight (BMI 25-30) men and women who drank 30mL of an apple vinegar-based drink (containing 1.5g acetic acid) each day for 12 weeks. Those who drank 15mL of the vinegar-based drink also saw reductions, whilst control subjects who did not take the drink saw no changes.

Writing in the Journal of Agricultural and Food Chemistry, researchers at Mizkan have also described studies in mice that highlight the mechanisms responsible for the changes in abdominal fat. Mice on a high-fat diet were divided into three groups and treated with 0.3% or 1.5% acetic acid solutions or water for 6 weeks. The groups treated with the acetic acid solutions consumed the same amount of food as the control group but showed reduced accumulation of body fat (about 10%) and hepatic lipids, with no changes in skeletal muscle weight. Significant increases in the expression of genes for peroxisome-proliferator-activated receptor-α (PPARα) and for fatty acid oxidation- and thermogenesis-related proteins were seen in the livers of the treatment groups. Similar up-regulation of gene expression was observed in vitro on addition of acetate to HepG2 cells. The effects were not observed in cells depleted of α2 5′-AMP-activated protein kinase (AMPK) by siRNA. The authors conclude that acetic acid suppresses accumulation of body fat and liver lipids by up-regulating genes for PPARα and fatty-acid-oxidation-related proteins in the liver via an α2 AMPK mediated process.

If larger clinical studies confirm fat reduction and positive effects on metabolism in overweight humans, vinegar could be set to take a share of a very large weight-loss market.

A number of human studies have linked lack of sleep to weight gain – decreased insulin sensitivity and glucose tolerance as well as disruption of the natural balance between the appetite hormones grehlin and leptin have been put forward to explain this link between disrupted sleep and weight gain. In studies in rodents, researchers at Merck have now shown that T-type calcium channels regulate both sleep and body weight maintenance. Mice lacking Ca_V3.1 T-type calcium channels were known to have altered sleep/wake patterns and the new study showed that these mice are also resistant to weight gain induced by a high fat diet.

Writing in the Journal of Clinical Investigation, the researchers report that the knock-out mice gained significantly less weight and had less body fat than their wild-type littermates when fed a high fat diet. The resistance to weight gain of the knock-out mice could not be fully explained by reduced food intake, an overall increase in activity or increased metabolic rate. In further studies, a selective T-type channel antagonist, TTA-A2, was shown to prevent, and even reverse, weight gain induced by a high fat diet, and also to improve body composition to greater extent than the widely used appetite suppressant, fenfluramine. TTA-A2, when dosed either prior to the sleep phase or during the wake phase, was found to promote sleep – a result which was unexpected since the knock-out mice have increased wake time compared with wild type animals. Although the reasons for the observed differences between pharmacological antagonism and genetic knock-out remain to be fully explained, the study highlights the potential for antagonism of T-type calcium channels as a novel weight loss strategy.

The authors suggest that the benefits of T-type calcium channel antagonists may be the result of better alignment of feeding patterns and the circadian rhythm and that sleep or circadian treatments may be of particular benefit for people struggling to lose weight or maintain weight loss because of poor diet.