An adipocyte hormone which functions as the afferent signal in a negative feedback loop regulating energy balance, has profound effects on glucose and lipid metabolisms. Lipodystrophic humans and mice have a complete or partial absence of adipose tissue and a secondary reduction of leptin. This is associated with insulin resistance and hepatic steatosis, which are corrected by leptin administration. This thesis aimed to define the site of leptin action and understand the molecular basis of leptin's insulin sensitizing and antisteatotic effects in lipodystrophy. To determine the site of leptin action, we treated lipodystrophic aP2-nSREBP-1c mice with a low dose of intracerebroventricular (icv) leptin. These studies showed that leptin acts on the brain mediating its peripheral effects indirectly via the CNS. The efferent pathways mediating leptin's peripheral effects are currently unknown. Using mice with a knockout of all three p-adrenergic receptors, we showed that sympathetic nervous system, specifically p-adrenergic receptors are in part responsible for mediating leptin's peripheral effects. Using microarray analysis in livers of lipodystrophic animals treated with either icv or subcutaneous leptin, we determined that central leptin administration repressed stearoyl-CoA desaturase-1 (SCD-1) mRNA levels and enzymatic activity. We then studied SCD-1 s role in leptin-mediated correction of hepatic steatosis and insulin resistance by generating aP2-nSREBP-1c mice homozygous for SCD-1 deletion. These animals had reduced hepatic steatosis. We showed that the mechanism by which SCD-1 deficiency leads to improved hepatic steatosis involved increased AMPK phosphorylation in parallel with decreased ACC activity. The latter resulted in decreased 1 malonyl CoA levels and increased CPT-1 activity. SCD-1 deficient lipodystrophic animals remained diabetic. To understand the mechanism of leptin's insulin sensitizing effects, we performed a leptin dose-response curve. We identified suboptimal leptin doses which improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice but did not substantially alter hepatic steatosis. One of these leptin doses improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K and Akt activity in liver suggesting that leptin improved insulin resistance via an insulindependent pathway. To identify leptin-regulated genes important in leptin's insulin sensitizing effects, we used cluster analysis of hepatic gene expression with several peripheral leptin doses.
","abstract_html":"<p>An adipocyte hormone which functions as the afferent signal in a negative feedback loop regulating energy balance, has profound effects on glucose and lipid metabolisms. Lipodystrophic humans and mice have a complete or partial absence of adipose tissue and a secondary reduction of leptin. This is associated with insulin resistance and hepatic steatosis, which are corrected by leptin administration. This thesis aimed to define the site of leptin action and understand the molecular basis of leptin's insulin sensitizing and antisteatotic effects in lipodystrophy. To determine the site of leptin action, we treated lipodystrophic aP2-nSREBP-1c mice with a low dose of intracerebroventricular (icv) leptin. These studies showed that leptin acts on the brain mediating its peripheral effects indirectly via the CNS. The efferent pathways mediating leptin's peripheral effects are currently unknown. Using mice with a knockout of all three p-adrenergic receptors, we showed that sympathetic nervous system, specifically p-adrenergic receptors are in part responsible for mediating leptin's peripheral effects. Using microarray analysis in livers of lipodystrophic animals treated with either icv or subcutaneous leptin, we determined that central leptin administration repressed stearoyl-CoA desaturase-1 (SCD-1) mRNA levels and enzymatic activity. We then studied SCD-1 s role in leptin-mediated correction of hepatic steatosis and insulin resistance by generating aP2-nSREBP-1c mice homozygous for SCD-1 deletion. These animals had reduced hepatic steatosis. We showed that the mechanism by which SCD-1 deficiency leads to improved hepatic steatosis involved increased AMPK phosphorylation in parallel with decreased ACC activity. The latter resulted in decreased 1 malonyl CoA levels and increased CPT-1 activity. SCD-1 deficient lipodystrophic animals remained diabetic. To understand the mechanism of leptin's insulin sensitizing effects, we performed a leptin dose-response curve. We identified suboptimal leptin doses which improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice but did not substantially alter hepatic steatosis. One of these leptin doses improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K and Akt activity in liver suggesting that leptin improved insulin resistance via an insulindependent pathway. To identify leptin-regulated genes important in leptin's insulin sensitizing effects, we used cluster analysis of hepatic gene expression with several peripheral leptin doses.</p>","abstract_has_math":false,"creators":["Asilmaz, Esra"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Jeffrey M. Friedman"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2004,"date_issued":"2004-01-01T08:00:00Z","date_published":"2004-01-01T08:00:00Z","updated_at":"2026-07-24T04:11:45Z","subjects":["diabetes","leptin","glucose homeostasis","hepatic steatosis","lipid metabolism","insulin resistance","Life Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/31","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Jeffrey M. 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Lipodystrophic humans and mice have a complete or partial absence of adipose tissue and a secondary reduction of leptin. This is associated with insulin resistance and hepatic steatosis, which are corrected by leptin administration. This thesis aimed to define the site of leptin action and understand the molecular basis of leptin's insulin sensitizing and antisteatotic effects in lipodystrophy. To determine the site of leptin action, we treated lipodystrophic aP2-nSREBP-1c mice with a low dose of intracerebroventricular (icv) leptin. These studies showed that leptin acts on the brain mediating its peripheral effects indirectly via the CNS. The efferent pathways mediating leptin's peripheral effects are currently unknown. Using mice with a knockout of all three p-adrenergic receptors, we showed that sympathetic nervous system, specifically p-adrenergic receptors are in part responsible for mediating leptin's peripheral effects. Using microarray analysis in livers of lipodystrophic animals treated with either icv or subcutaneous leptin, we determined that central leptin administration repressed stearoyl-CoA desaturase-1 (SCD-1) mRNA levels and enzymatic activity. We then studied SCD-1 s role in leptin-mediated correction of hepatic steatosis and insulin resistance by generating aP2-nSREBP-1c mice homozygous for SCD-1 deletion. These animals had reduced hepatic steatosis. We showed that the mechanism by which SCD-1 deficiency leads to improved hepatic steatosis involved increased AMPK phosphorylation in parallel with decreased ACC activity. The latter resulted in decreased 1 malonyl CoA levels and increased CPT-1 activity. SCD-1 deficient lipodystrophic animals remained diabetic. To understand the mechanism of leptin's insulin sensitizing effects, we performed a leptin dose-response curve. We identified suboptimal leptin doses which improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice but did not substantially alter hepatic steatosis. One of these leptin doses improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K and Akt activity in liver suggesting that leptin improved insulin resistance via an insulindependent pathway. To identify leptin-regulated genes important in leptin's insulin sensitizing effects, we used cluster analysis of hepatic gene expression with several peripheral leptin doses.
"]},{"key":"dc:title","label":"Title","values":["Site and Mechanism of Leptin's Antisteatotic and Insulin Sensitizing Actions in Lipodystrophic Liver"]}]}],"canonical_facts":{"dc:contributor":["Jeffrey M. Friedman"],"dc:creator":["Asilmaz, Esra"],"dc:description.abstract":["An adipocyte hormone which functions as the afferent signal in a negative feedback loop regulating energy balance, has profound effects on glucose and lipid metabolisms. Lipodystrophic humans and mice have a complete or partial absence of adipose tissue and a secondary reduction of leptin. This is associated with insulin resistance and hepatic steatosis, which are corrected by leptin administration. This thesis aimed to define the site of leptin action and understand the molecular basis of leptin's insulin sensitizing and antisteatotic effects in lipodystrophy. To determine the site of leptin action, we treated lipodystrophic aP2-nSREBP-1c mice with a low dose of intracerebroventricular (icv) leptin. These studies showed that leptin acts on the brain mediating its peripheral effects indirectly via the CNS. The efferent pathways mediating leptin's peripheral effects are currently unknown. Using mice with a knockout of all three p-adrenergic receptors, we showed that sympathetic nervous system, specifically p-adrenergic receptors are in part responsible for mediating leptin's peripheral effects. Using microarray analysis in livers of lipodystrophic animals treated with either icv or subcutaneous leptin, we determined that central leptin administration repressed stearoyl-CoA desaturase-1 (SCD-1) mRNA levels and enzymatic activity. We then studied SCD-1 s role in leptin-mediated correction of hepatic steatosis and insulin resistance by generating aP2-nSREBP-1c mice homozygous for SCD-1 deletion. These animals had reduced hepatic steatosis. We showed that the mechanism by which SCD-1 deficiency leads to improved hepatic steatosis involved increased AMPK phosphorylation in parallel with decreased ACC activity. The latter resulted in decreased 1 malonyl CoA levels and increased CPT-1 activity. SCD-1 deficient lipodystrophic animals remained diabetic. To understand the mechanism of leptin's insulin sensitizing effects, we performed a leptin dose-response curve. We identified suboptimal leptin doses which improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice but did not substantially alter hepatic steatosis. One of these leptin doses improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K and Akt activity in liver suggesting that leptin improved insulin resistance via an insulindependent pathway. To identify leptin-regulated genes important in leptin's insulin sensitizing effects, we used cluster analysis of hepatic gene expression with several peripheral leptin doses.
"],"dc:identifier":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/31"],"dc:subject":["diabetes","leptin","glucose homeostasis","hepatic steatosis","lipid metabolism","insulin resistance","Life Sciences"],"dc:title":["Site and Mechanism of Leptin's Antisteatotic and Insulin Sensitizing Actions in Lipodystrophic Liver"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T04:11:45Z"}