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-The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls (n ϭ 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n ϭ 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-␥ (PPAR␥). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity. visceral fat; lipolysis; gluconeogenic enzymes; messenger ribonucleic acid; dogs VISCERAL ADIPOSITY HAS BEEN ASSOCIATED with insulin resistance, glucose intolerance, dyslipidemia, and cardiovascular disease (15,18,20). The liver has specifically been implicated as a primary site of insulin resistance observed with visceral obesity. The mechanisms relating visceral fat accumulation and hepatic insulin resistance are not well known, but several possible factors might be implicated. One hypothesis states that visceral fat secretes several substances [tumor necrosis factor-␣ (TNF-␣) (22) and/or resistin (37) or decreased adiponectin (2)] that may induce hepatic insulin resistance. The alternative "portal hypothesis" posits a high rate of lipolysis of visceral adipose tissue leading to increased delivery of free fatty acids (FFA) to the liver via the portal vein, thus contributing to increased fat accumulation and ...

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Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S I ), and pancreatic ␤-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n ‫؍‬ 10), RIS (5 mg/day; n ‫؍‬ 10), or gelatin capsules (n ‫؍‬ 6) for 4 -6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (؉91 ؎ 20%; P ‫؍‬ 0.000001) reflecting marked increases in subcutaneous (؉106 ؎ 24%; P ‫؍‬ 0.0001) and visceral (؉84 ؎ 22%; P ‫؍‬ T he introduction of atypical antipsychotics in psychopharmacology represented a major advance in the treatment of schizophrenia, providing an effective therapy for both positive and negative symptoms of psychosis while minimizing the extrapyramidal effects characteristic of earlier therapeutic options. Indeed, these medications are widely prescribed (ϳ3% of the U.S. population) for treatment of schizophrenia, as well as bipolar disorder, depression, and dementia.In the face of their widespread use, concern has arisen regarding treatment-associated weight gain and apparent increased diabetes risk (1-3). It is unclear whether weight gain is a direct effect of the drug or secondary to behavioral changes, such as increased sedation associated with pharmacotherapy. But regardless of its causality, obesity is a significant public health concern and is a well-documented risk factor for type 2 diabetes as well as other chronic diseases, such as cancer and atherosclerosis (4 -6). Nonetheless, diabetes risk with antipsychotic use has also been reported in the absence of significant weight gain (7-9).Evidence linking atypical antipsychotics to metabolic dysregulation is largely based on case reports and retrospective analyses, which note a disproportionately greater number of patients developing fasting hyperglycemia and new-onset diabetes or exhibiting exacerbation of preexisting diabetes soon after the initiation of atypical antipsychotic treatment (10 -15). Henderson et al. (14) reported that Ͼ30% of schizophrenic patients receiving clozapine developed diabetes within a 5-year follow-up, and those with preexisting diabetes required increased insulin dosing. Federal Drug Administration reports (10), based in part on the Medwatch Surveillance Program, provide further evidence of the excessive occurrence of new-onset diabetes and exacerbation of preexisting disease with clozapine compared with disease incidence in untreated individuals. More recently, olanzapine (OLZ) and risperidone (RIS), which collectively account for Ͼ80% of all drugs prescribed of their class of atypical antipsychotics, have also been associated with metabolic abnormalities, though OLZ is generally linked to greater relative risk for diabetes (11,16) and more marked obesity (3,11,17) compared with RIS (12,13,18).It is indeed challenging to study the actions of antipsy-

RN. Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia. Am J Physiol Endocrinol Metab 292: E1590 -E1598, 2007. First published January 30, 2007; doi:10.1152/ajpendo.00669.2006.-Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model. obesity; diurnal IT HAS TRADITIONALLY BEEN BELIEVED that the development of insulin resistance associated with obesity is due to an increase in the level of circulating free fatty acids (FFA) resulting from an impairment of insulin's ability to suppress lipolysis in adipose tissue (4,7,21). Increased FFA levels have been shown to decrease insulin's ability both to suppress hepatic glucose output and to promote peripheral glucose uptake, which can then result in an increase in fasting glucose (14,15). It has traditionally been thought that this increase in fasting glucose resulting from insulin resistance is responsible for compensatory hyperinsulinemia. Thus increasing FFA by lipid infusion results in development of insulin resistance and a compensatory increase in insulin levels (9) in addition to causing mild fasting hyperglycemia due to stimulation of both glycogenolysis and gluconeogenesis (40). However, studies in several different animal models as well as in humans have not consistently demonstrated increases in fasting FFA or glucose during the development of insulin resistance and hyperinsulinemia during obesity (16,20,22,38,41). Studies conducted in our own laboratory (25, 31) using the fat-fed dog model have found development of insulin resistance with concomitant increases of 90 -150% in basal insulin with no significant changes in either fastin...