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The effect of dietary ethanol on metabolic fates of glucose and ethanol, and activities of lipoprotein lipase and hormone‐sensitive lipase in several tissues of miniature pigs were determined in vitro. Ethanol and glucose were used at similar rates for fatty acid synthesis in liver and brain and CO2 production in liver. Ethanol was preferred over glucose for fatty acid and CO2 production in ileal mucosal cells. Glucose was the preferred substrate for lipogenesis and oxidation to CO2 in adipose tissue and skeletal muscle, and for oxidation to CO2 in brain. Dietary ethanol decreased glucose and ethanol conversion to fatty acids in ileal mucosa and brain, respectively. Dietary ethanol had no effect on the capacity of liver, adipose tissue, and skeletal muscle to convert either glucose or ethanol to long‐chain fatty acids. The capacity to oxidize ethanol, but not glucose, to CO2 in liver was increased by dietary ethanol. No dietary ethanol effect was observed in other tissues. The capacity for removal of plasma triglycerides (based on lipoprotein lipase activity) tended to increase in adipose tissue and skeletal muscle of pigs fed ethanol. Mobilization of long‐chain fatty acids from adipose tissue (based on hormone‐sensitive lipase activity), triglyceride concentration in plasma, and percentage of lipid in liver remained unchanged when ethanol was fed. Livers of ethanol‐fed pigs, however, were larger than livers of control pigs. Our results indicate that feeding miniature pigs 21–37% of total caloric intake as ethanol causes significant metabolic adaptations of lipid metabolism in liver and ileal mucosa, but not in adipose tissue, skeletal muscle, and brain. The ethanol feeding, however, did not cause fatty livers or hyperlipidemia.

OBJECTIVE: Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. METHODS: In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity. RESULTS: We identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder. CONCLUSIONS: OTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis.

Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD ad libitum (AL), as well as receiving HFD limited to the amount of calories eaten by controls (pair-fed (PF) group). Body weight, food intake, adiposity and plasma leptin were lower in ACE inhibitor or ARB-treated groups over 28 days compared with HFD untreated mice. Short-term treatment with captopril led to increased EE relative to the level in the PF group. After 28 days, EE was lower in both captopril-treated and PF mice compared with AL, but the effect was greater in the captopril-treated group. Adiponectin was elevated in captopril-treated mice, but not in PF mice, after both 2 and 28 days. Additionally, acute RAS blockade in HFD-fed mice reduced mRNA expression for MCP-1, IL-6, TLR4, and leptin in adipose tissue relative to values in untreated groups. These data demonstrate that ACE inhibition and angiotensin receptor blockade reduce food intake to produce weight loss and suggest that the anti-inflammatory effects of ACE inhibition may be independent of weight loss.

CRF is recognised for its actions on pituitary ACTH release, but also has direct effects within the brain which are important in mediating physiological responses to stress. Behavioral effects of CRF include increased locomotor activity and inhibition of food intake and its actions on metabolism are mediated mainly by activation of the sympathetic nervous system. CRF appears to be important in the regulation of energy balance and body weight, influencing both food intake and sympathetically-mediated thermogenesis. A defect in the synthesis or release of CRF has been implicated in the development of obesity in laboratory animals, since the condition is alleviated by adrenalectomy, hypophysectomy or exogenous CRF treatment. Recent data have revealed an additional role for CRF as a mediator of the neuroendocrine and metabolic responses to immune signals, particularly cytokines. The central actions of CRF are independent of the pituitary but may involve release of proopiomelanocortin products within the brain. CRF is thus emerging as an important integrator of the physiological responses to stress, infection and immunity, a finding which may have important implications for future therapies.

Abstract Ethanol-induced sleep onset times, sleep times and blood alcohol levels upon awakening were measured in mice fed an essential fatty acid deficient, Purina Chow or unsaturated fat diet for nine months. These values in animals fed the essential fatty acid deficient and Purina Chow diets did not differ, but mice fed the unsaturated fat diet had longer sleep times and lower blood alcohol levels upon awakening than mice fed essential fatty acid deficient or Purina Chow diets. Crude brain mitochondrial fractions isolated from mice fed the essential fatty acid deficient diet had decreased levels of docosahexaenoic [22:6(n-3)] and increased levels of eicosatrienoic [20:3(n-9)], docosatrienoic [22:3(n-9)] and docosapentaenoic [22:5(n-6)] acids compared to mice fed the Purina Chow diet. The unsaturated fat diet decreased 22:6(n-3) and increased 22:5(n-6) compared to the Purina Chow dietary regimen. The longer sleep times and lower blood alcohol levels found in mice fed the unsaturated fat diet probably resulted from an artifact due to the obesity of the mice fed this diet and from the hinderance of obesity to the righting reflex (our measure of ethanol potency). We conclude that the alteration of several polyunsaturated fatty acid components in the brain has little or no influence on the sensitivity of the nervous system to alcohol.

The Melanocortin system is involved in animal models of obesity and anorexia-cachexia and MC4 receptors (MC4-R) are currently a target system for the development of drugs aimed to treat obesity and eating disorders in humans. Previous evidence suggest that feeding peptides might lack their orexigenic activity while stimulate ethanol intake. The present study comparatively evaluated food intake (4-h interval) in Sprague-Dawley (SD) rats drinking ethanol (6% w/v, 2 bottle choice paradigm) (EE group) and ethanol-naïve (EN) rats in response to bilateral infusion of the selective MC4-R antagonist HS014 (0, 0.02 or 0.05 μg/0.5μl/site) or the selective MC4-R agonist cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 μg/0.5μl/site), into the lateral hypothalamus (LH), the nucleus accumbens (NAc), or the ventral tegmental area (VTA). The main findings in the study are: 1) LH-infusions of the MC4-R antagonist increased and the agonist reduced feeding and total calories consumed, while ethanol intake remained unaltered. 2) NAc- and VTA-infusions of the selective agonist reduced food, ethanol and total calories intake. 3) NAc- and VTA-infusions of the MC4-R antagonist increased feeding in EN rats, but not in EE animals which showed a mild increase in ethanol intake, while total calories consumed remained unaltered. Present data show that having ethanol available reduces feeding elicited by NAc and VTA-MC4-R blockade. Additionally, while MC4-R signalling in the LH appears to modulate homeostatic aspects of feeding, it may contribute to non-homeostatic aspects of ingestive behaviours in the VTA and the NAc.