Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

Thrifty metabolism that favors fat storage after caloric restriction: a role for skeletal muscle phosphatidylinositol-3-kinase activity and AMP-activated protein kinase

Energy conservation directed at accelerating body fat recovery (or catch-up fat) contributes to obesity relapse after slimming and to excess fat gain during catch-up growth after malnutrition. To investigate the mechanisms underlying such thrifty metabolism for catch-up fat, we tested whether during refeeding after caloric restriction rats exhibiting catch-up fat driven by suppressed thermogenesis have diminished skeletal muscle phosphatidylinositol-3-kinase (PI3K) activity or AMP-activated protein kinase (AMPK) signaling—two pathways required for hormone-induced thermogenesis in ex vivo muscle preparations. The results show that during isocaloric refeeding with a low-fat diet, at time points when body fat, circulating free fatty acids, and intramyocellular lipids in refed animals do not exceed those of controls, muscle insulin receptor substrate 1-associated PI3K activity (basal and in vivo insulin-stimulated) is lower than that in controls. Isocaloric refeeding with a high-fat diet, which exacerbates the suppression of thermogenesis, results in further reductions in muscle PI3K activity and in impaired AMPK phosphorylation (basal and in vivo leptin-stimulated). It is proposed that reduced skeletal muscle PI3K/AMPK signaling and suppressed thermogenesis are interdependent. Defective PI3K or AMPK signaling will reduce the rate of substrate cycling between de novo lipogenesis and lipid oxidation, leading to suppressed thermogenesis, which accelerates body fat recovery and furthermore sensitizes skeletal muscle to dietary fat-induced impairments in PI3K/AMPK signaling.—Summermatter, S., Mainieri, D., Russell, A. P., Seydoux, J., Montani, J. P., Buchala, A., Solinas, G., Dulloo, A. G. Thrifty metabolism that favors fat storage after caloric restriction: a role for skeletal muscle phosphatidylinositol-3-kinase activity and AMP-activated protein kinase.

Dietary electrolytes are related to mood

Dietary therapies are routinely recommended to reduce disease risk; however, there is concern they may adversely affect mood. We compared the effect on mood of a low-sodium, high-potassium diet (LNAHK) and a high-calcium diet (HC) with a moderate-sodium, high-potassium, high-calcium Dietary Approaches to Stop Hypertension (DASH)-type diet (OD). We also assessed the relationship between dietary electrolytes and cortisol, a stress hormone and marker of hypothalamic–pituitary–adrenal (HPA) axis activity. In a crossover design, subjects were randomized to two diets for 4 weeks, the OD and either LNAHK or HC, each preceded by a 2-week control diet (CD). Dietary compliance was assessed by 24 h urine collections. Mood was measured weekly by the Profile of Mood States (POMS). Saliva samples were collected to measure cortisol. The change in mood between the preceding CD and the test diet (LNAHK or HC) was compared with the change between the CD and OD. Of the thirty-eight women and fifty-six men (mean age 56·3 (sem 9·8) years) that completed the OD, forty-three completed the LNAHK and forty-eight the HC. There was a greater improvement in depression, tension, vigour and the POMS global score for the LNAHK diet compared to OD (P < 0·05). Higher cortisol levels were weakly associated with greater vigour, lower fatigue, and higher levels of urinary potassium and magnesium (r 0·1–0·2, P < 0·05 for all). In conclusion, a LNAHK diet appeared to have a positive effect on overall mood.

Effect of the glycemic index of carbohydrates on day-long (10 h) profiles of plasma glucose, insulin, cholecystokinin and ghrelin

Background: Low glycemic index (GI) carbohydrates have been linked to increased satiety. The drive to eat may be mediated by postprandial changes in glucose, insulin and gut peptides.
Objective: To investigate the effect of a low and a high GI diet on day-long (10 h) blood concentrations of glucose, insulin, cholecystokinin (CCK) and ghrelin (GHR).
Design: Subjects (n¼12) consumed a high and a low GI diet in a randomized, crossover design, consisting of four meals that were matched for macronutrients and fibre, and differed only in carbohydrate quality (GI). Blood was sampled every 30–60 min and assayed for glucose, insulin, CCK and GHR.
Results: The high GI diet resulted in significantly higher glucose and insulin mean incremental areas under the curve (IAUC, P¼0.027 and P¼0.001 respectively). CCK concentration was 59% higher during the first 7 h of the low GI diet (394±95 pmol/l min) vs the high GI diet (163±38 pmol/l min, P¼0.046), but there was no difference over 10 h (P¼0.224). GHR concentration was inversely correlated with insulin concentration (Pearson correlation 0.48, P¼0.007), but did not differ significantly between the low and high GI diets.
Conclusions: Mixed meals of lower GI are associated with lower day-long concentrations of glucose and insulin, and higher CCK after breakfast, morning tea and lunch. This metabolic profile could mediate differences in satiety and hunger seen in some, but not all, studies.

Interaction of dietary fibre, carbohydrate metabolism and diabetes in the rat

It is currently accepted that the most appropriate diet in the treatment of non-insulin-dependent diabetes mellitus "e;NIDDM"e; is high in carbohydrates, high in fibre and low in fat. Dietary fibre reduces the rate of carbohydrate absorption, which may have a beneficial effect on insulin action. Furthermore, high fibre diets also increase the amount of carbohydrates which are not absorbed from the small intestine. These malabsorbed carbohydrates are fermented by the bacterial population in the large intestine, producing short chain fatty acids "e;SCFA"e;, including propionate, which has been shown to alter liver carbohydrate metabolism. This thesis investigated the actions of slowed carbohydrate absorption and carbohydrate malabsorption in streptozotocin-induced "e;STZ"e; diabetic rats. High carbohydrate diet supplemented with guar gum, a soluble dietary fibre, fed to STZ diabetic rats improved insulin sensitivity. investigation of the alterations in the stomach and small intestine demonstrated that guar increased the viscosity of the meal in the intestine. The action of increased fermentation, producing more propionate, was investigated by supplementing propionate into the diets of STZ diabetic rats or when perfused into isolated rat livers. No changes in insulin action or liver glucose metabolism were measured. in addition, it was shown that guar gum reduces food intake in STZ diabetic rats. Mild reductions in food intake in STZ diabetic rats were shown to increase insulin action. In summary, STZ diabetic rats fed high carbohydrate, high fibre diets reductions in food consumption and slowed carbohydrate absorption are important factors which may lower blood glucose concentrations and increase insulin action. increased SCFA production is unlikely to contribute significantly to the improvements in insulin action.

Lipid composition of cashmere goat fibres

This study examined the differences in the chemical composition, particularly fatty acids, of the lipid extracted from the fibre of bucks, does and castrated goats. The study provides a more detailed understanding of the chemical composition of buck fibre lipid and how it varies throughout the year, and also details the effect of body region and nutrition on the production and chemical composition of lipid from buck fibre. Lipid was extracted with either petroleum ether (non-polar) or chloroform/methanol azeotrope (polar) and analysed by gas chromatography and gas chromatography-mass spectrometry. The more polar solvent system extracted larger amounts of lipid and more of each individual fatty acid. The following buck specific ethyl branched fatty acids were identified: 2-ethylhexanoic, 4-ethylhexanoic, 2-ethyloctanoic, 4-ethyloctanoic, 6-ethyloctanoic, 2-ethyldecanoic, 4-ethyldecanoic, 2-ethyldodecanoic, 6-ethyldodecanoic, 4-ethyldodecanoic, 2-ethyltetradecanoic, 6-ethyltetradecanoic, 4-ethyltetradecanoic, 2-ethylhexadecanoic and 4-ethyloctadecanoic acids. Of these buck specific fatty acids only 4-ethylhexanoic (T), 4-ethyloctanoic, 4-ethyldecanoic, 4-ethyldodecanoic, 6-ethyldodecanoic (T), 4-ethyltetradecanoic, 2-ethylhexadecanoic (T) and 4-ethylhexadecanoic acids have been previously identified or tentatively identified (T) in buck fibre extracts. This shows that the chemical composition of buck fibre lipid is more complex than previously reported, and that it may be more difficult than previously thought to artificially duplicate the odour of the buck. Buck fibre samples had lower average concentrations of 2-methylpropanoic, 2-methylbutanoic, iso-pentadecanoic, anteiso-pentadecanoic, iso-hexadecanoic, anteiso-heptadecanoic, iso-octadecanoic and anteiso-nonadecanoic acids as compared with fibre samples from does, spayed does, or wethers that were castrated at one month of age. The reduced concentrations of these fatty acids in buck fibre extracts were likely to be due to the synthesis of ethyl branched derivatives of iso and anteiso fatty acids. Buck fibre samples had higher concentrations of benzoic acid as compared with fibre samples from does, spayed does, or wethers that were castrated at one month of age. The significance of these results is that non buck specific fatty acids may also make a contribution to the odour of bucks. When fibre samples were collected at various times throughout the year, it was found that the bucks had increased amounts of lipid and ethyl branched fatty acids in fibre samples shorn from March to September, as compared with fibre samples shorn in November and January. The increase in the amount of lipid and ethyl branched fatty acids corresponded with both the rutting period of the buck and the period when the buck odour was increased. This suggests that ethyl branched fatty acids could be pheromones. The variation in lipid content and fatty acid composition was also examined between fibre samples collected from different body regions of the buck during April, as alterations in sebaceous gland activity around the neck during rutting have been reported. It was found that the average amount of lipid in the neck region of the bucks was not statistically higher than the average amounts in the midside and hind regions. However, the ethyl branched fatty acid concentrations were statistically higher in the fibre from around the neck as compared with the fibre from the other body regions, which is consistent with the odour of the buck being most pronounced around the head and neck region. The lipid content and composition of fibre samples from bucks fed high and low quality diets (lucerne and pangola grass, respectively) was examined to determine the effect of nutrition on buck specific components. The high quality diet increased the amount of lipid and ethyl branched fatty acids in fibre samples collected in April from the neck, midside and hind regions, as compared with fibre samples from the corresponding body regions from bucks fed the low quality diet. Thus it may be possible for the pheromone levels of bucks to be increased by simply providing them with good nutrition. The lipid content and ethyl branched fatty acid concentrations of fibre samples increased earlier in the year for the lucerne fed bucks as compared with the pangola grass fed bucks. The lucerne fed bucks had increased concentrations of ethyl branched fatty acids in fibre samples shorn during December to June (6 months) whereas the pangola grass fed bucks had increased concentrations of ethyl branched fatty acids in fibre samples shorn during April to August (4 months). These observations show that good nutrition can result in both the earlier production of ethyl branched fatty acids and an extended period when ethyl branched fatty acids are produced. This suggests that nutrition can be used to manipulate pheromone levels in the buck. The period when the ethyl branched fatty acids were increased corresponded with the period when the plasma luteinizing hormone (LH) and testosterone concentrations, odour and sebaceous gland volume of the bucks were increased, which supports the assumption that ethyl branched fatty acids are involved in odour production and act as pheromones.

Effects of dietary constituents on coronary heart disease risk factors

Coronary Heart Disease (CHD) is a major cause of death in Western countries. Mediterranean and Asian populations have a lower risk of death from CHD compared to Westernised population, as do vegetarian versus omnivorous populations. Dietary constituents of traditional diets consumed by these populations are thought to influence both the classical risk factors for CHD, and the more recently identified risk factors, such as oxidative modification of low density lipoprotein (LDL), LDL particle size, arterial compliance and haemostatic factors. The aim of this thesis was to examine the effects of several food components, particularly soybean and monounsaturated fat (MUFA), on CHD risk factors through 3 carefully controlled dietary interventions, and a cross-sectional study. A randomised crossover dietary intervention study was conducted in 42 healthy males to investigate the effect on CHD risk factors of replacing lean meat with tofu, a soybean product regularly consumed by Asian populations, while controlling all other dietary factors. The tofu diet resulted in significantly lower total cholesterol and triacylglycerol levels compared to the lean meat diet, and LDL particles that were more resistant to in vitro oxidative modification. However, insulin, fibrinogen, factor VII, and lipoprotein (a) were not significantly different on the 2 diets. A postprandial study was subsequently conducted to investigate any acute effects of a tofu test meal on the oxidative modification of LDL in 16 male subjects. There was no significant difference between the susceptibility of LDL to oxidative modification before and after the tofu meal. Twenty eight healthy subjects completed a separate randomised crossover dietary intervention comparing a high MUFA fat diet, using an Australian high oleic sunflower oil, with a low fat, high carbohydrate diet on CHD risk factors. The high MUFA oil diet significantly increased high density lipoprotein cholesterol compared to the low fat diet as well as producing LDL that were more resistant to oxidative modification. Neither the size of the LDL particle nor arterial compliance were significantly different on the 2 diets. Twelve matched pairs of vegetations and omnivores were also studies to compare the habitual diet of a low and higher risk population group, to compare their risk factors and identify dietary constituents that may explain the differences. The vegetarians consumed less saturated fat (SFA) and dietary cholesterol while consuming more polyunsaturated fat, dietary fibre and vitamin E compared to omnivores. The vegetarians had lower total cholesterol, LDL cholesterol and triacylglycerol levels compared to the omnivores and had LDL particles that were more resistant to in vitro oxidation. These findings contribute to our knowledge about the dietary constituents that can alter some CHD risk factors in healthy subjects, and which could reduce the risk of developing CHD. Investigations in high risk groups might reveal even more benefits.

VVP808 is a novel agent that improves glucose tolerance in DIO mice

As the prevalence of diabetes mellitus continues to increase, there is an urgent need to discover new, effective treatment strategies to combat this disorder. In this study, we tested a novel agent, VVP808, which we previously demonstrated has insulin-sensitising properties (as measured by an increase in insulin-stimulated glucose uptake in 3T3-L1 adipocytes). A dose-ranging study was performed (10-100mg/kg/d) in C57BL/6J mice that had been fed a high-fat diet (45% of energy) for 12 weeks. VVP808 was administered by single daily oral gavage for a period of 16 days. Body weight, food intake and water intake were measured daily, whilst fasting blood glucose and plasma insulin levels were measured at the beginning and end of the study, with an intra-peritoneal glucose tolerance test (ipGTT) performed on day -1 and day 13. Administration of VVP808 to diet-induced obese (DIO) mice caused a strong dose-dependent improvement in glucose tolerance. There was a 34-42% reduction in the blood glucose area under the curve (AUC) at doses of 20mg/kg, 50mg/kg and 100mg/kg VVP808 (p=0.02-0.005). Administration of VVP808 resulted in a small but significant reduction in body weight in the 50mg/kg and 100mg/kg treated animals relative to vehicle (p=0.01 and 0.001 respectively). This decrease in body weight was associated with a reduction in food intake for the 100mg/kg treated animals only. Epididymal fat pad weight was significantly reduced in animals treated with 100mg/kg VVP808 (p=0.01). Furthermore, treatment with VVP808 for 16 days resulted in a highly significant dose-dependent reduction in fasting blood glucose levels relative to vehicle treated animals (p= 0.01-0.001). In conclusion, our data showed that VVP808 acts in a dose-dependent manner to reduce fasting blood glucose levels and improve glucose tolerance. These data suggest that VVP808 is an interesting new agent with potential for development as a novel therapeutic for type 2 diabetes.

Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome

Background and Aim:  Reduction of short-chain poorly absorbed carbohydrates (FODMAPs) in the diet reduces symptoms of irritable bowel syndrome (IBS). In the present study, we aimed to compare the patterns of breath hydrogen and methane and symptoms produced in response to diets that differed only in FODMAP content.
Methods:  Fifteen healthy subjects and 15 with IBS (Rome III criteria) undertook a single-blind, crossover intervention trial involving consuming provided diets that were either low (9 g/day) or high (50 g/day) in FODMAPs for 2 days. Food and gastrointestinal symptom diaries were kept and breath samples collected hourly over 14 h on day 2 of each diet.
Results:  Higher levels of breath hydrogen were produced over the entire day with the high FODMAP diet for healthy volunteers (181 ± 77 ppm.14 h vs 43 ± 18; mean ± SD P < 0.0001) and patients with IBS (242 ± 79 vs 62 ± 23; P < 0.0001), who had higher levels during each dietary period than the controls (P < 0.05). Breath methane, produced by 10 subjects within each group, was reduced with the high FODMAP intake in healthy subjects (47 ± 29 vs 109 ± 77; P = 0.043), but was not different in patients with IBS (126 ± 153 vs 86 ± 72). Gastrointestinal symptoms and lethargy were significantly induced by the high FODMAP diet in patients with IBS, while only increased flatus production was reported by healthy volunteers.
Conclusions:  Dietary FODMAPs induce prolonged hydrogen production in the intestine that is greater in IBS, influence the amount of methane produced, and induce gastrointestinal and systemic symptoms experienced by patients with IBS. The results offer mechanisms underlying the efficacy of the low FODMAP diet in IBS.

Impact of secondary salinisation on freshwater ecosystems : effect of experimentally increased salinity on an intermittent floodplain wetland

Intermittent wetlands are particularly at risk from secondary salinisation because salts are concentrated during drawdown. We conducted a field experiment to examine the effect of adding salt at two different concentrations (to achieve nominal conductivities of 1000 μS cm–1 (low salt) and 3000 μS cm–1 (high salt)) on water quality, freshwater plants and epiphytic diatoms in an intermittent wetland during a 3.3-month drawdown. Conductivity increased to 3000 and 8500 μS cm–1 in low-salt and high-salt treatments respectively. Salt was apparently lost to the sediments, causing protons to be released from the sediments and reducing water column pH from 6.9 to 5.5 in the low-salt treatment and to 4.0 in the high-salt treatments. Forty days after adding the salt, biomass, %cover and flower production in Potamogeton cheesmanii were significantly reduced, whereas Amphibromus fluitans was not significantly affected. The salt effect on Triglochin procera was intermediate between the other two macrophytes. Significant reductions in the density, species richness and diversity of epiphytic diatoms occurred in the high-salt, but not in the low-salt, treatments. Our work shows that increases in salinity, and thus conductivity (up to 8500 μS cm–1), in low-alkalinity intermittent wetlands can change water quality, with significant adverse effects on some macrophyte and diatom communities.

Carbohydrate intake strategies to enhance endurance exercise performance

While elite Olympic distance triathletes consume adequate carbohydrate pre-competition, many fail to meet suggested guidelines during actual competition. Furthermore, metabolic adaptations that occur in response to training appear similar under varying conditions of carbohydrate availability. However, daily training with high carbohydrate availability increases the use of carbohydrate consumed during exercise.

Possible changes of pore size during nanofiltration

The textile industry plays an important role in the world economy as well as our daily life. However, the industry consuming a large quantity of water and generating huge amount of wastewater are unsustainable to the conservation of our precious resources and environment and need improvement. The wastewater, especially the one from spent cotton reactive dyebaths, contains high salt content, various dyes and high alkalinity. This study was carried out to investigate the feasibility of membrane filtration treating spent cotton reactive dye baths. A stirred cell with nanofiltration membrane was used aiming at reusing the reclaimed water. Spent dyebath solutions were synthesized containing hydrolyzed C. I. Reactive Black 5 and sodium chloride. When a piece of membrane was used repeatedly it was expected the flux would decrease after each usage due to fouling of impurities. However, it was found that the water flux increased while dye rejection decreased after each run. At pH 10, the dye rejection decreased significantly. It was proposed that the pore sizes of membrane might have changed during membrane filtration. An equation was derived calculating the possible changes of pore sizes.

How the ladybird got its spots : effects of resource limitation on the honesty of aposematic signals

Prey species often possess defences (e.g. toxins) coupled with warning signals (i.e. aposematism). There is growing evidence that the expression of aposematic signals often varies within species and correlates with the strength of chemical defences. This has led to the speculation that such signals may be 'honest', with signal reliability ensured by the costliness of producing or maintaining aposematic traits. We reared larval seven-spot ladybirds (Coccinella septempunctata) on a Low or High aphid diet and measured the effects on warning signal expression (elytral carotenoid pigmentation, conspicuousness, spot size), levels of defensive alkaloids (precoccinelline, coccinelline), and relationships between these traits. High-diet individuals had greater total precoccinelline levels, and elytra carotenoid concentrations at adulthood which was detectable to a typical avian predator. However, larval diet did not significantly affect adult body mass or size, spot size or coccinelline levels. Elytra carotenoid concentrations correlated positively with total precoccinelline levels in both diet groups and sexes. However, the relationship between elytra carotenoid concentrations and total levels of coccinelline depended on sex: in both diet groups, elytra carotenoids and coccinelline levels were positively correlated in females, but negatively correlated in males. Spot size and coccinelline levels correlated positively in Low-diet individuals, but negatively in High-diet individuals. These results point to physiological linkages between components of aposematism, which are modulated by resource (i.e. food) availability and affect the honesty of signals. Developmental diet, but also sex, influenced the relationships between signals and toxin levels. Ladybirds are sexually size dimorphic, and thus in comparison with males, females may be more susceptible to resource limitation and more likely to be honest signallers. © 2012 The Authors. Functional Ecology © 2012 British Ecological Society.

Fructose containing sugars modulate mRNA of lipogenic genes ACC and FAS and protein levels of transcription factors ChREBP and SREBPIc with no effect on body weight or liver fat

The aim of this study was to determine the effects of high-glucose, high-fructose and high-sucrose diets on weight gain, liver lipid metabolism and gene expression of proteins involved with hepatic fat metabolism. Rats were fed a diet containing either 60% glucose, 60% fructose, 60% sucrose, or a standard chow for 28 days. Results indicated that high-fructose and high-sucrose diets were associated with higher mRNA levels of gene transcripts involved with fat synthesis; ACC, FAS and ChREBP, with no change in SREBP-1C mRNA. The protein level of ChREBP and SREBP1c was similar in liver homogenates from all groups, but were higher in nuclear fractions from the liver of high-fructose and high-sucrose fed rats. The mRNA level of gene transcripts involved with fat oxidation was the same in all three diets, whilst a high-fructose diet was associated with greater amount of mRNA of the fat transporter CD36. Despite the changes in mRNA of lipogenic proteins, the body weight of animals from each group was the same and the livers from rats fed high-fructose and high-sucrose diets did not contain more fat than control diet livers. In conclusion, changing the composition of the principal monosaccharide in the diet to a fructose containing sugar elicits changes in the level of hepatic mRNA of lipogenic and fat transport proteins and protein levels of their transcriptional regulators; however this is not associated with any changes in body weight or liver fat content.

Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity

Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high-fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin, and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.